Fluoroalkyl-oxadiazoles and uses thereof

ABSTRACT

Provided herein are compounds identified as inhibitors of HDAC6 activity having the formula: 
                         
or a pharmaceutically acceptable salt thereof, that can be used to treat various diseases and disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2020/066439, filed Dec. 21, 2020, which claims the benefit of andpriority to U.S. Provisional Application Ser. No. 63/064,516, filed Aug.12, 2020, U.S. Provisional Application Ser. No. 63/027,602, filed May20, 2020, and U.S. Provisional Application Ser. No. 62/951,853, filedDec. 20, 2019, the contents of each of which are hereby incorporated byreference in their entirety for all purposes.

BACKGROUND

Histone deacetylase (HDAC) are a class of enzymes with deacetylaseactivity with a broad range of genomic and non-genomic substrates. Thereare eleven zinc-dependent HDAC enzymes classified based on sequenceidentity and catalytic activity.

Histone deacetylase inhibitors have been described and used in varioustherapeutic applications, including oncology, neurodegeneration,autoimmune disease, chemotherapy-induced peripheral neuropathy andcardiac indications. However, many HDAC inhibitors are non-specific(i.e., they inhibit the activity of more than one HDAC with more or lessthe same affinity). When administered to humans, these so-calledpan-HDAC inhibitors (e.g., SAHA and Panabinostat) exhibit significantadverse effects such as fatigue, nausea, diarrhea and thrombocytopenia.Thus, there is a need for HDAC inhibitors that selectively target aparticular HDAC, such as HDAC6.

SUMMARY

The present disclosure is directed to compounds that selectively inhibitHDAC6 activity and uses thereof in treating various diseases anddisorders. For example, the present disclosure provides small moleculesand compositions as well as therapeutic compositions and uses ofspecific small molecule compounds.

In one aspect, the present disclosure provides compound of Formula (I),or a pharmaceutically acceptable salt thereof:

R¹ is selected from the group consisting of:

R^(a) is selected from the group consisting of H, halo, C₁₋₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² and R³ are independently selected from the group consisting of H,halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl,each of which is optionally substituted, or R² and R³ together with theatom to which they are attached form a cycloalkyl or heterocyclyl;R⁴ and R⁵ are independently selected from the group consisting of H,—(SO₂)R², —(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl, arylheteroaryl,alkylenearyl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl,and alkoxy, each of which is optionally substituted, or R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, each of which is optionally substituted; X¹ is selectedfrom the group consisting of S, O, NH and NR⁶, wherein R⁶ is selectedfrom the group consisting of C₁-C₆ allyl, alkoxy, haloalkyl, cycloalkyland heterocyclyl;R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, haloalkyl,cycloalkyl and heterocyclyl;Y is selected from the group consisting of CR², O, N, S, SO, and SO₂,wherein when Y is O, S, SO, or SO₂, R⁵ is not present and when R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, Y is CR² or N; andn is selected from 0, 1, and 2.

In some embodiments, the present disclosure provides a compound ofFormula (Ia) or pharmaceutically acceptable salt thereof:

In some embodiments, the present disclosure provides a compound ofFormula (Ib) or pharmaceutically acceptable salt thereof:

In some embodiments, the present disclosure provides a compound ofFormula (Ic) or a pharmaceutically acceptable salt thereof:

In another aspect, the present disclosure provides a compound of Formula(II) or pharmaceutically acceptable salt thereof:

whereinR¹ is selected from the group consisting of:

R^(a) is selected from the group consisting of H, halo, C₁-₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² is selected from the group consisting of H, aryl, heteroaryl,cycloalkyl, heterocyclyl, haloalkyl, alkoxy, —(CH₂)_(m)aryl,—(CH₂)_(m)N(R³)aryl, —(CH₂)_(m)Oaryl, —(CH₂)_(m)(SO₂)aryl,—(CH₂)_(m)heteroaryl, —(CH₂)_(m)N(R³)heteroaryl, —(CH₂)_(m)Oheteroaryl,—(CH₂)_(m)cycloalkyl, —(CH₂)_(m)heterocyclyl, —(CH₂)_(m)(COOH),—(CH₂)_(m)(COOR³), —(CH₂)_(m)(CONR³R⁴), —(CH₂)m(NR³SO₂NR³R⁴), and—(CH₂)_(m)(SO₂R³), each of which is optionally substituted, wherein m isselected from 1, 2, or 3;R³ and R⁴ are independently selected from the group consisting of H,aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyl each of which isoptionally substituted, or R³ and R⁴ together with the atom to whichthey are attached form an optionally substituted heterocyclyl;andX¹, X² and X³ are independently selected from C and N, with the provisothat X¹ and X² cannot both be N.

In some embodiments, the present disclosure provides a compound ofFormula (III) or pharmaceutically acceptable salt thereof:

whereinR¹ is selected from the group consisting of:

R^(a) is selected from the group consisting of H, halo, C₁-₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² and R³ are independently selected from the group consisting of H,halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, orR² and R³ together with the atom to which they are attached form acycloalkyl or heterocyclyl;R⁴ and R⁵ are selected from the group consisting of H, —(SO₂)R²,—(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl, arylheteroaryl, heteroaryl,cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, or R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl;X¹, X², and X³ are selected from the group consisting of: (1) X¹ isCR^(a), X² is N, and X³ is CR³; (2) X¹ is N, X² is CR^(a), and X³ isCR^(a); (3) X¹ is CR^(a), X² is CR^(a), and X³ is N; (4) X¹ is N, X² isCR^(a), and X³ is N; (5) X¹ is CR^(a), X² is N, and X³ is N; and (6) X¹is N, X² is N, and X³ is CR^(a);Y is selected from the group consisting of CR², O, N, S, SO, and SO₂,wherein when Y is O, S, SO, or SO₂, R⁵ is not present and when R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, Y is CR² or N; andn is 1 or 2.

In some embodiments, the present disclosure provides a compound ofFormula (IV) or pharmaceutically acceptable salt thereof:

or

whereinR¹ is selected from the group consisting of:

R^(a) is selected from the group consisting of H, halo, C₁₋₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² and R³ are independently selected from the group consisting of H,halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl,each of which is optionally substituted, or R² and R³ together with theatom to which they are attached form a cycloalkyl or heterocyclyl;R⁴ and R⁵ are independently selected from the group consisting of H,—(SO₂)R², —(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl, arylheteroaryl,heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, eachof which is optionally substituted, or R⁴ and R⁵ together with the atomto which they are attached form a cycloalkyl or heterocyclyl;X¹ is selected from the group consisting of O, S, NH, or NR⁶, wherein R⁶is selected from the group consisting of C₁-C₆ alkyl, alkoxy, haloalkyl,cycloalkyl and heterocyclyl; andY is selected from the group consisting of CR², O, N, S, SO, and SO₂,wherein when Y is O, S, SO, or SO₂, R⁵ is not present and when R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, Y is CR² or N; andn is selected from 0, 1, or 2.

In some embodiments, the present disclosure provides therapeutic methodscomprising use of the compounds disclosed herein (i.e., Formula (I),Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Id-1),Formula (Id-2), Formula (Id-3), Formula (Id-4), Formula (Ie), Formula(Ie-1), Formula (If), Formula (If-1), Formula (Ig), Formula (Ig-1),Formula (Ih), Formula (Ih-1), Formula (Ii), Formula (Ii-1), Formula(Ij), Formula (Ij-1), Formula (Ik), Formula (Ik-1), Formula (Ik-2),Formula (Ik-3), Formula (II), Formula (III), Formula (IVa), and Formula(IVb)) in treating patients suffering from aberrant cell proliferativedisorders, β-amyloid protein aggregation, polyglutamine proteinaggregation, neurodegeneration, stroke, psychiatric disorders,depression, autoimmune disease, inflammatory diseases (e.g.,inflammatory bowel disorder or disease (IBD), irritable bowel syndrome(IBS), Crohn's disease, ulcerative colitis (UC), glaucoma, psoriasis,pyoderma gangrenosum, psoriatic arthritis, rheumatoid arthritis,spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis,sepsis, acute kidney injury, lung injury, ischemia reperfusion injury'of solid organs), heart failure with preserved ejection fraction(HFpEF), indications including, but not limited to inflammasomeformation leading to cell death and inflammation, chemotherapy-inducedneuropathy, Charcot-Marie-Tooth disease, idiopathic pulmonary fibrosis,erectile dysfunction, hypertension, muscular dystrophy, and/or cardiacdiseases or disorders. Proliferative disorders include, but are notlimited to, malignant gliomas, breast cancer, basal cell carcinoma,medulloblastomas, neuroectodermal tumors, and ependymomas. Cardiacdiseases or disorders that can be treated with the compounds of thepresent disclosure include, but art not limited to, coronary heartdisease, cardiomyopathy, endocarditis, congenital cardiovasculardefects, congestive heart failure, dilated cardiomyopathy, hypertrophiccardiomyopathy, valvular heart disease, myocardial infarction,congestive heart failure, long QT syndrome, atrial arrhythmia,ventricular arrhythmia, diastolic heart failure, systolic heart failure,cardiac valve disease, cardiac valve calcification, left ventricularnon-compaction, ventricular septal defect, and ischemia.

DEFINITIONS

While the following terms are believed to be well understood by one ofordinary skill in the art, the following definitions are set forth tofacilitate explanation of the presently disclosed subject matter.

The term “a” or “an” refers to one or more of that entity; for example,“an HDAC6 inhibitor” refers to one or more HDAC6 inhibitors or at leastone HDAC6 inhibitor. As such, the terms “a” (or “an”), “one or more” and“at least one” are used interchangeably herein. In addition, referenceto “an inhibitor” by the indefinite article “a” or “an” does not excludethe possibility that more than one of the inhibitors is present, unlessthe context clearly requires that there is one and only one of theinhibitors.

The term “pharmaceutically acceptable salts” include those obtained byreacting the active compound functioning as a base, with an inorganic ororganic acid to form a salt, for example, salts of hydrochloric acid,sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonicacid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid,hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylicacid, mandelic acid, carbonic acid, etc. Those skilled in the art willfurther recognize that acid addition salts may be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods.

“Alkyl” or “alkyl group” refers to a fully saturated, straight orbranched hydrocarbon chain having from one to twelve carbon atoms, andwhich is attached to the rest of the molecule by a single bond. Alkylscomprising any number of carbon atoms from 1 to 12 are included. Analkyl comprising up to 12 carbon atoms is a C₁-C₁₂ alkyl, an alkylcomprising up to 10 carbon atoms is a C₁-C₁₀ alkyl, an alkyl comprisingup to 6 carbon atoms is a C₁-C₆ alkyl and an alkyl comprising up to 5carbon atoms is a C₁-C₅ alkyl. A C₁-C₅ alkyl includes C₅ alkyls, C₄alkyls, C₃ alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl). A C₁-C₆ alkylincludes all moieties described above for C₁-C₅ alkyls but also includesC₆ alkyls. A C₁-C₁₀ alkyl includes all moieties described above forC₁-C₅ alkyls and C₁-C₆ alkyls, but also includes C₇, C₈, C₉ and C₁₀alkyls. Similarly, a C₁-C₁₂ alkyl includes all the foregoing moieties,but also includes C₁₁ and C₁₂ alkyls. Non-limiting examples of C₁-C₁₂alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwisespecifically in the specification, an alkyl group can be optionallysubstituted.

“Alkylene” or “alkylene chain” refers to a fully saturated, straight orbranched divalent hydrocarbon chain radical, and having from one totwelve carbon atoms. Non-limiting examples of C₁-C₁₂ alkylene includemethylene, ethylene, propylene, n-butylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto a radical group (e.g., those described herein) through a single bond.The points of attachment of the alkylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkylene chain can be optionally substituted.

“Alkenyl” or “alkenyl group” refers to a straight or branchedhydrocarbon chain having from two to twelve carbon atoms, and having oneor more carbon-carbon double bonds. Each alkenyl group is attached tothe rest of the molecule by a single bond. Alkenyl group comprising anynumber of carbon atoms from 2 to 12 are included. An alkenyl groupcomprising up to 12 carbon atoms is a C₂-C₁₂ alkenyl, an alkenylcomprising up to 10 carbon atoms is a C₂-C₁₀ alkenyl, an alkenyl groupcomprising up to 6 carbon atoms is a C₂-C₆ alkenyl and an alkenylcomprising up to 5 carbon atoms is a C₂-C₅ alkenyl. A C₂-C₅ alkenylincludes C₅ alkenyls, C₄ alkenyls, C₃ alkenyls, and C₂ alkenyls. A C₂-C₆alkenyl includes all moieties described above for C₂-C₅ alkenyls butalso includes C₆ alkenyls. A C₂-C₁₀ alkenyl includes all moietiesdescribed above for C₂-C₅ alkenyls and C₂-C₆ alkenyls, but also includesC₇, C₈, C₉ and C₁₀ alkenyls. Similarly, a C₁₂ alkenyl includes all theforegoing moieties, but also includes C₁₁ and C₁₂ alkenyls. Non-limitingexamples of C₂-C₁₂ alkenyl include ethenyl (vinyl), 1-propenyl,2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl,2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl,1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl,7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl,5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl,2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl,7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl,2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl,7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl.Unless stated otherwise specifically in the specification, an alkylgroup can be optionally substituted.

“Alkenylene” or “alkenylene chain” refers to an unsaturated, straight orbranched divalent hydrocarbon chain radical having one or more olefinsand from two to twelve carbon atoms. Non-limiting examples of C₂-C₁₂alkenylene include ethenylene, propenylene, n-butenylene, and the like.The alkenylene chain is attached to the rest of the molecule through asingle bond and to a radical group (e.g., those described herein)through a single bond. The points of attachment of the alkenylene chainto the rest of the molecule and to the radical group can be through onecarbon or any two carbons within the chain. Unless stated otherwisespecifically in the specification, an alkenylene chain can be optionallysubstituted.

“Alkynyl” or “alkynyl group” refers to a straight or branchedhydrocarbon chain having from two to twelve carbon atoms, and having oneor more carbon-carbon triple bonds. Each alkynyl group is attached tothe rest of the molecule by a single bond. Alkynyl group comprising anynumber of carbon atoms from 2 to 12 are included. An alkynyl groupcomprising up to 12 carbon atoms is a C₂-C₁₂ alkynyl, an alkynylcomprising up to 10 carbon atoms is a C₂-C₁₀ alkynyl, all alkynyl groupcomprising up to 6 carbon atoms is a C₂-C₆ alkynyl and an alkynylcomprising up to 5 carbon atoms is a C₂-C₅ alkynyl. A C₂-C₅ alkynylincludes C₅ alkynyls, C₄ alkynyls, C₃ alkynyls, and C₂ alkynyls. A C₂-C₆alkynyl includes all moieties described above for C₂-C₅ alkynyls butalso includes C₆ alkynyls. A C₂-C₁₀ alkynyl includes all moietiesdescribed above for C₂-C₅ alkynyls and C₂-C₆ alkynyls, but also includesC₇, C₈, C₉ and C₁₀ alkynyls. Similarly, a C₂-C₁₂ alkynyl includes allthe foregoing moieties, but also includes C₁₁ and C₁₂ alkynyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethynyl, propynyl,butynyl, pentynyl and the like. Unless stated otherwise specifically inthe specification, an alkyl group can be optionally substituted.

“Alkynylene” or “alkynylene chain” refers to an unsaturated, straight orbranched divalent hydrocarbon chain radical having one or more alkynesand from two to twelve carbon atoms. Non-limiting examples of C₂-C₁₂alkynylene include ethynylene, propynylene, n-butynylene, and the like.The alkynylene chain is attached to the rest of the molecule through asingle bond and to a radical group (e.g., those described herein)through a single bond. The points of attachment of the alkynylene chainto the rest of the molecule and to the radical group can be through anytwo carbons within the chain having a suitable valency. Unless statedotherwise specifically in the specification, an alkynylene chain can beoptionally substituted.

“Alkoxy” refers to a group of the formula —O R_(a) where R_(a) is analkyl, alkenyl or alknyl as defined above containing one to twelvecarbon atoms. Unless stated otherwise specifically in the specification,an alkoxy group can be optionally substituted.

“Aryl” refers to a hydrocarbon ring system comprising hydrogen, 6 to 18carbon atoms and at least one aromatic ring, and which is attached tothe rest of the molecule by a single bond. For purposes of thisdisclosure, the aryl can be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which can include fused or bridged ringsystems. Aryls include, but are not limited to, aryls derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene,indene, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene,and triphenylene. Unless stated otherwise specifically in thespecification, the “aryl” can be optionally substituted.

“Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ringsstructure, wherein the atoms which form the ring are each carbon, andwhich is attached to the rest of the molecule by a single bond.Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring.Carbocyclic rings include aryls and cycloalkyl, cycloalkenyl, andcycloalkynyl as defined herein. Unless stated otherwise specifically inthe specification, a carbocyclyl group can be optionally substituted.

“Carbocyclylalkyl” refers to a radical of the formula —R_(b)—R_(d) whereR_(b) is an alkylene, alkenylene, or alkynylene group as defined aboveand R_(d) is a carbocyclyl radical as defined above. Unless statedotherwise specifically in the specification, a carbocyclylalkyl groupcan be optionally substituted.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclicfully saturated hydrocarbon consisting solely of carbon and hydrogenatoms, which can include fused or bridged ring systems, having fromthree to twenty carbon atoms (e.g., having from three to ten carbonatoms) and which is attached to the rest of the molecule by a singlebond. Monocyclic cycloalkyls include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Polycyclic cycloalkyls include, for example, adamantyl, norbornyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, a cycloalkyl groupcan be optionally substituted.

“Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon consisting solely of carbon and hydrogen atoms, having oneor more carbon-carbon double bonds, which can include fused or bridgedring systems, having from three to twenty carbon atoms, preferablyhaving from three to ten carbon atoms, and which is attached to the restof the molecule by a single bond. Monocyclic cycloalkenyls include, forexample, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, andthe like. Polycyclic cycloalkenyls include, for example,bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise statedspecifically in the specification, a cycloalkenyl group can beoptionally substituted.

“Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon consisting solely of carbon and hydrogen atoms, having oneor more carbon-carbon triple bonds, which can include fused or bridgedring systems, having from three to twenty carbon atoms, preferablyhaving from three to ten carbon atoms, and which is attached to the restof the molecule by a single bond. Monocyclic cycloalkynyl include, forexample, cycloheptynyl, cyclooctynyl, and the like. Unless otherwisestated specifically in the specification, a cycloalkynyl group can beoptionally substituted.

“Haloalkyl” refers to an alkyl, as defined above, that is substituted byone or more halo radicals, e.g., trifluoromethyl, difluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless statedotherwise specifically in the specification, a haloalkyl group can beoptionally substituted.

“Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stablesaturated, unsaturated, or aromatic 3- to 20-membered ring whichconsists of two to nineteen carbon atoms and from one to six heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur, andwhich is attached to the rest of the molecule by a single bond.Heterocyclycl or heterocyclic rings include heteroaryls,heterocyclylalkyls, heterocyclylalkenyls, and hetercyclylalkynyls.Unless stated otherwise specifically in the specification, theheterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclicring system, which can include fused or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heterocyclyl can be optionallyoxidized; the nitrogen atom can be optionally quaternized; and theheterocyclyl can be partially or fully saturated. Examples of suchheterocyclyl include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group can be optionally substituted.

“Heteroaryl” refers to a 5- to 20-membered ring system comprisinghydrogen atoms, one to nineteen carbon atoms, one to six heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur, atleast one aromatic ring, and which is attached to the rest of themolecule by a single bond. For purposes of this disclosure, theheteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which can include fused or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl can be optionallyoxidized; the nitrogen atom can be optionally quaternized. Examplesinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,berizo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl,2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyiimidinyl,1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group can be optionallysubstituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)—R_(e)where R_(b) is an alkylene, alkenylene, or alkynylene group as definedabove and R_(e) is a heterocyclyl radical as defined above. Unlessstated otherwise specifically in the specification, aheterocycloalkylalkyl group can be optionally substituted.

The term “substituted” used herein means any of the groups describedherein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl,carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl,heterocyclyl, and/or heteroaryl) wherein at least one hydrogen atom isreplaced by a bond to a non-hydrogen atoms such as, but not limited to:a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups suchas hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom ingroups such as thiol groups, thioalkyl groups, sulfone groups, sulfonylgroups, and sulfoxide groups; a nitrogen atom in groups such as amities,amides, alkylamines, dialkylamines, arylamines, alkylarylamines,diarylamines, N-oxides, imides, and enamines; a silicon atom in groupssuch as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilylgroups, and triarylsilyl groups; and other heteroatoms in various othergroups. “Substituted” also means any of the above groups in which one ormore hydrogen atoms are replaced by a higher-order bond (e.g., a double-or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl,carboxyl, and ester groups; and nitrogen in groups such as imines,oximes, hydrazones, and nitriles. For example, “substituted” includesany of the above groups in which one or more hydrogen atoms are replacedwith —NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and—SO2NR_(g)R_(h). “Substituted” also means any of the above groups inwhich one or more hydrogen atoms are replaced with —C(═O)R_(g),—C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h). Inthe foregoing, R_(g) and R_(h) are the same or different andindependently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl,cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl. “Substituted” further means any of the above groups inwhich one or more hydrogen atoms are replaced by a bond to an amino,cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl,alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl,haloalkynyl, heterocyclyl, heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroaryl alkyl group. In addition, each of theforegoing substituents can also be optionally substituted with one ormore of the above substituents.

As used herein, the symbol “

” (hereinafter can be referred to as “a point of attachment bond”)denotes a bond that is a point of attachment between two chemicalentities, one of which is depicted as being attached to the point ofattachment bond and the other of which is not depicted as being attachedto the point of attachment bond. For example, “

” indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond. Furthermore, the specific pointof attachment to the non-depicted chemical entity can be specified byinference. For example, the compound CH₃—R³, wherein R³ is H or “

” infers that when R³ is “XY”, the point of attachment bond is the samebond as the bond by which R³ is depicted as being bonded to CH₃.

DETAILED DESCRIPTION

Histone deacetylases (“HDAC”) are a class of enzymes with deacetylaseactivity with a broad range of genomic and non-genomic substrates. Thereare eleven Zinc-dependent HDAC enzymes classified based on sequenceidentity and catalytic activity (Haberland et al., 2009).

Histone deacetylase inhibitors have been described as a therapeuticagents in oncology (Yoon and Eom, 2016), neurodegeneration (Butler etal., 2010) autoimmune disease (Choi et al., 2018), chemotherapy-inducedperipheral neuropathy (Krukowski et al., 2017) and cardiac indications(Zhang et al., 2002). Given the role of nuclear HDACs on regulating genetranscription, inhibition of these class of targets is known to havepleiotropic effects in various cell types; most notably resulting incell toxicities. Therefore, limiting the toxicity of pan-HDAC inhibitorshas been a major obstacle in wide-spread utilization for this class ofcompounds. In addition, significant adverse effects of pan-HDACinhibitors (e.g. SAHA and Panabinostat) has been observed in the clinicincluding fatigue, nausea, diarrhea and thrombocytopenia (Subramanian etal., 2010).

In the cardiac-indication space, most studies have utilized pan-HDACinhibitors (e.g. SAHA, TSA and Givinostat) for the treatment ofpressure-overload rodent models including transverse aortic constriction(TAC) (Cao et al., 2011), hypertension in Dahl salt-sensitive rats(Jeong et al., 2018) and myocardial infarction (Nagata et al., 2019). Inaddition, HDAC6-selective inhibitors have been used to ameliorate theeffects of pressure overload in rodent models (Demos-Davies et al.,2014) and provide protection against proteotoxicity in a transgeniccardiomyopathy mouse model (McLendon et al., 2014).

HDAC6 belongs to the class IIb enzyme and contains two catalyticdomains, a ubiquitin binding domain and a cytoplasmic retention domain(Haberland et al., 2009). HDAC6 is predominately a cytoplasmic enzymeand its best-characterized substrates include tubulin, HSP90 andcortactin (Brindisi et al., 2019).

Pharmacological inhibition of HDAC6 blocks its deacetylase activity,thus resulting in hyperacetylation of its substrates, most notablytubulin (Hubbert et al., 2002).

HDAC6-selective inhibitors are known to have reduced cytotoxicity due tothe cytoplasmic nature of HDAC6 substrates and reduced effects onnuclear targets (including H3K9 and c-MYC) and on global transcription(Nebbioso et al., 2017).

Hydroxamic acids are zinc chelators and have been used extensively inthe development of pan- and HDAC-selective inhibitors. However, mosthydroxamic-acid based HDAC inhibitors either lack the desiredselectivity or show poor bioavailability with a poor pharmacokineticprofile (Butler et al., 2010; Santo et al., 2012).

The present disclosure provides compounds that, in some embodiments,selectively inhibit HDAC6. In some embodiments, the selectivity ratio ofHDAC6 over HDAC1 is from about 5 to about 30,0000, e.g., about 5, about10, about 20, about 30, about 40, about 50, about 60, about 70, about80, about 90, about 100, about 1000, about 2000, about 3000, about 4000,about 5000, about 6000, about 7000, about 8000, about 9000, about10,000, about 15,000, about 20,000, about 25,000, or about 30,000,including all values and ranges therebetween.

Compounds of the Disclosure

In one aspect, the present disclosure provides a compound of Formula (A)or a pharmaceutically acceptable salt thereof:

wherein:{circle around (A)} is selected from the group consisting

R¹ is selected from the group consisting of:

R² and R³ are independently selected from the group consisting of H,halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl eachof which is optionally substituted, or R² and R³ together with the atomto which they are attached form a cycloalkyl or heterocyclyl;R⁴ and R⁵ are independently selected from the group consisting of H,—(SO₂)NR², —(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl, arylheteroaryl,alkylenearyl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl,and alkoxy, each of which is optionally substituted, or R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, each of which is optionally substituted;R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, haloalkyl,cycloalkyl and heterocyclyl;when {circle around (A)} is

X¹ is selected from the group consisting of S, O, NH and NR⁶, wherein R⁶is selected from the group consisting of C₁-C₆ alkyl alkoxy, haloalkyl,cycloalkyl and heterocyclyl;when {circle around (A)} is

X¹, X² and X³ are independently selected from C and N, with the provisothat X¹ and X² cannot both be N;when {circle around (A)}

X¹, X², and X³ are selected from the group consisting of: (1) X¹ is CH,X² is N, and X³ is CH; (2) X¹ is N, X² is CH, and X³ is CH; (3) X¹ isCH, X² is CH, and X³ is N; (4) X¹ is N, X² is CH, and X³ is N; (5) X¹ isCH, X is N, and X³ is N; and (6) X¹ is N, X² is N, and X³ is CH;R^(a) is selected from the group consisting of H, halo, C₁₋₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;Y is selected from the group consisting of CR², O, N, S, SO, and SO₂,wherein when Y is O, S, SO, or SO₂, R⁵ is not present and when R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, Y is CR² or N; andn is selected from 0, 1, and 2.

In some embodiments, the compound of Formula (A) is selected from thegroup consisting of:

Compounds of Formula (I)

In one aspect, the present disclosure provides a compound of Formula (I)or pharmaceutically acceptable salt thereof:

whereinR¹ is selected from the group consisting of:

R^(a) is selected from the group consisting of H, halo, C₁₋₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² and R³ are independently selected from the group consisting of H,halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl,each of which is optionally substituted, or R² and R³ together with theatom to which they are attached form a cycloalkyl or heterocyclyl;R⁴ and R⁵ are independently selected from the group consisting of H,—(SO₂)R², —(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl, arylheteroaryl,heteroaryl, alkylenearyl, cycloalkyl, heterocyclyl, alkyl haloalkyl, andalkoxy, each of which is optionally substituted, or R⁴ and R⁵ togetherwith the atom to which they are attached form a cycloalkyl orheterocyclyl, each of which is optionally substituted:R⁹ is selected from the group consisting of C₁-C₆ alkyl, haloalkyl,cycloalkyl and heterocyclyl;X¹ is selected from the group consisting of S, O, NH and NR⁶, wherein R⁶is selected from the group consisting of C₁-C₆ alkyl, alkoxy, haloalkyl,cycloalkyl and heterocyclyl;Y is selected from the group consisting of CR², O, N, S, SO, and SO₂,wherein when Y is O, S, SO, or SO₂, R⁵ is not present and when R⁴ and R⁵together with the atom to which they are attached form an optionallysubstituted cycloalkyl or an optionally substituted heterocyclyl, Y isCR² or N; andn is selected from 0, 1, and 2.

In some embodiments of Formula (I), n is 0. In some embodiments, n is 1.In some embodiments, n is 2. In some embodiments, n is 0 or 1. In someembodiments, n is 1 or 2. In some embodiments, n is 0 or 2.

In some embodiments of Formula (I), X¹ is O. In some embodiments, X¹ isS. In some embodiments, X¹ is NH. In some embodiments, X¹ is NR⁶. Insome embodiments, X¹ is selected from the group consisting of S, O, andNR⁶. In some embodiments, X¹ is selected from the group consisting of S,O, and NCH₃. In some embodiments, X¹ is S or O. In some embodiments, X¹is S or NR⁶. In some embodiments, is C₁-C₆ alkyl.

In some embodiments of Formula (I), R² and R³ are H.

In some embodiments of Formula (I), Y is N, CR², or O. In someembodiments, Y is N or O. In some embodiments, Y is N. In someembodiments, Y is CR². In some embodiments, Y is O.

In some embodiments, R⁴ and R⁵ are independently selected from the groupconsisting of H, —(SO₂)R², —(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl,arylheteroaryl, heteroaryl, alkylenearyl, cycloalkyl,alkylenecycloalkyl, heterocyclyl, alkyleneheterocyclyl, alkyl,haloalkyl, and alkoxy, each of which is optionally substituted, or R⁴and R⁵ together with the atom to which they are attached form acycloalkyl or heterocyclyl, each of which is optionally substituted

In some embodiments of Formula (I), R⁴ is selected from the groupconsisting of —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —(SO₂)NR2R³, —SO₂-alkyl, and —SO₂-cycloalkyl, each ofwhich is optionally substituted. In some embodiments, R⁴ is selectedfrom the group consisting of —C(O)-alkyl, —C(O)-cycloalkyl, —SO₂-alkyl,—SO₂-haloalkyl, —SO₂-cycloalkyl, and —(SO₂)NR²R³, each of which isoptionally substituted. In some embodiments, aryl is optionallysubstituted with one or more halogens. In some embodiments of Formula(I), R⁴ is selected from the group consisting of —SO₂alkyl,—SO₂haloalkyl, or —SO₂cycloalkyl. In some embodiments of Formula (I), R⁴is selected from the group consisting of —SO₂Me, —SO₂Et, and —SO₂-cPr.In some embodiments of Formula (I), R⁴ is —SO₂Me or —SO₂Et. In someembodiments, R² and R³ are each independently -C₁₋₅alkyl. In someembodiments, R² and R³ taken together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclyl. In someembodiments, the optionally substituted heterocyclyl is morpholine,thiomorpholine, or thiomorpholine 1,1-dioxide.

In some embodiments of Formula (I), R⁵ is aryl, heteroaryl, orcycloalkyl, each of which is optionally substituted.

In some embodiments, R⁵ is aryl. In some embodiments, aryl is

wherein R^(b) is one or more selected from the group consisting ofhalogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, alkylene-Ohaloalkyl,cycloalkyl, heterocyclyl aryl, heteroaryl, alkylnitrile, or CN. In someembodiments, the haloalkyl is selected from CF₃, CF₂CH₃, CHF₂, or CH₂F.In some embodiments, the alkyl is a -C₁₋₅alkyl. In some embodiments, -C₁₋₅alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. In someembodiments, methyl, ethyl, propyl, i-propyl, butyl, or t-butyl isoptionally substituted with OH. In some embodiments, the cycloalkyl is aC₃₋₆cycloalkyl. In some embodiments, the aryl is a phenyl. In someembodiments, the heteroaryl is 5- or 6-membered heteroaryl having 1, 2,or 3 heteroatoms selected from N, O, and S. In some embodiments, theheterocyclyl is a 4- to 7-member heterocyclyl with 1 or 2 heteroatomsselected from N, O, and S. In some embodiments, the Ohaloalkyl isselected from OCF₃, OCHF₂, or OCH₂F. In some embodiments, the Oalkyl isO-methyl, O-ethyl, O-propyl, O-i-propyl, O-butyl, or O-t-butyl.

In some embodiments, R⁵ is heteroaryl. In some embodiments, heteroarylis an optionally substituted 5- to 14-membered heteroaryl. In someembodiments, heteroaryl is an optionally substituted 5- to 14-memberedheteroaryl having 1, 2, or 3 heteroatoms selected from the groupconsisting of N, O, and S. In some embodiments, the optionallysubstituted 5- to 14-membered heteroaryl is selected from the groupconsisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl,quinoxalinyl, cinnolinyl, indolizinyl, azaindolizinyl, indolyl,azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl, benzthiophenyl,imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl. In someembodiments, the optionally substituted 5- to 14-membered heteroaryl isselected from the group consisting of pyrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, benzoxazolyl, imidazopyridinyl, andimidazopyrazinyl. In some embodiments, R⁵ is

wherein R^(b) is one or more selected from the group consisting ofhalogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, alkylene-Ohaloalkyl,cycloalkyl, heterocyclyl aryl, heteroaryl, alkylnitrile, or CN. In someembodiments, the haloalkyl is selected from CF₃, CF₂CH₃, CHF₂, or CH₂F.In some embodiments, the alkyl is a -C₁₋₅alkyl. In some embodiments,-C₁₋₅alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. Insome embodiments, methyl, ethyl, propyl, i-propyl, butyl, or t-butyl isoptionally substituted with OH. In some embodiments, the cycloalkyl is aC₃₋₆cycloalkyl. In some embodiments, the aryl is a phenyl. In someembodiments, the heteroaryl is 5- or 6-membered heteroaryl having 1, 2,or 3 heteroatoms selected from N, O, and S. In some embodiments, theheterocyclyl is a 4- to 7-member heterocyclyl with 1 or 2 heteroatomsselected from N, O, and S. In some embodiments, the Ohaloalkyl isselected from OCF₃, OCHF₂, or OCH₂F. In some embodiments, the Oalkyl isO-methyl, O-ethyl, O-propyl, O-i-propyl, O-butyl, or O-t-butyl.

In some embodiments, R⁵ is cycloalkyl. In some embodiments, cycloalkylis a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of whichis optionally substituted. In some embodiments, the optionallysubstituted cycloalkyl is

In some embodiments, R⁵ is selected from the group consisting of phenyl,3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl,3,4-difluorophenyl, and 2,6-ditluorophenyl. In some embodiments, R⁵ iscyclopropyl. In some embodiments, R⁵ selected from the group consistingof pyridin-3-yl and 1-methylindazole-6-yl. In some embodiments, R⁵ isselected from the group consisting of H, phenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl,cyclopropyl, pyridin-3-yl, 1-methylindazole-6-yl,3,3-difluorocyclobutyl, and 4,4-difluorocyclohexyl. In some embodiments,R⁵ is 3-chlorophenyl. In some embodiments R⁵ is H. In some embodiments,R⁵ is

In some embodiments, R⁵ is —CH₂CH₂Ph. In some embodiments, R⁵ isselected from the group consisting of H, aryl, heteroaryl, alkylenearyl,cycloalkyl, heterocyclyl, alkyl, and haloalkyl, each of which isoptionally substituted, or R⁴ and R⁵ together with the atom to whichthey are attached form an optionally substituted heterocyclyl.

In some embodiments of Formula (I), R⁵ is optionally substituted withone or more halogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, cycloalkyl,heterocyclyl aryl, or heteroaryl. In some embodiments, the haloalkyl isselected from CF₃, CHF₂, or CH₂F. In some embodiments, the alkyl is a-C₁₋₅alkyl. In some embodiments, -C₁₋₅alkyl is methyl, ethyl, propyl,i-propyl, butyl, or t-butyl. In some embodiments, the cycloalkyl is aC₃₋₆cycloalkyl. In some embodiments, the aryl is a phenyl. In someembodiments, the heteroaryl is 5- or 6-membered heteroaryl having 1, 2,or 3 heteroatoms selected from N, O, and S. In some embodiments, theheterocyclyl is a 4- to 7-member heterocyclyl with 1 or 2 heteroatomsselected from N, O, and S. In some embodiments, the Ohaloalkyl is OCF₃,OCHF₂, or OCH₂F. In some embodiments, the Oalkyl is O-methyl, O-ethyl,O-propyl, O-i-propyl, O-butyl, or O-t-butyl.

In some embodiments of Formula (I), R⁴ is H or -C₁₋₅alkyl and R⁵ isaryl. In some embodiments, R⁴ is H or -C₁₋₅alkyl and R⁵ is heteroaryl.In some embodiments, R⁴ is H or -C₁₋₅alkyl and R⁵ is cycloalkyl. In someembodiments, the -C₁₋₅alkyl is methyl, ethyl, or propyl. In someembodiments, the -C₁₋₅alkyl is methyl. In some embodiments, the aryl isoptionally substituted phenyl. In some embodiments, the heteroaryl is a5- to 14-membered heteroaryl having 1, 2, or 3 heteroatoms selected fromthe group consisting of N, O, and S. In some embodiments, the optionallysubstituted 5- to 14-membered heteroaryl is selected from the groupconsisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl,quinoxalinyl, cinnolinyl, indolizinyl, azaindolizinyl, indolyl,azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl, benzthiophenyl,imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl. In someembodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. Insome embodiments, the 5-membered heteroaryl is optionally substitutedpyrazolyl, imidazolyl, or oxazolyl. In some embodiments, the 6-memberedheteroaryl is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl,or pyridazinyl. In some embodiments, cycloalkyl is optionallysubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In someembodiments, aryl is optionally substituted with one or moresubstituents selected from the group consisting of halogen,C₁₋₆haloalkyl, C₁₋₆alkyl, O-C₁₋₆haloalkyl, O-C₁₋₆haloalkyl, orC₃₋₆cycloalky. In some embodiments, heteroaryl is optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, C₁₋₆haloalkyl, C₁₋₆alkyl, O-C₁₋₆alkyl, O-C₁₋₆haloalkyl, orC₃₋₆cycloalky.

In some embodiments of Formula (I), R⁴ is —(CO)R² and R⁵ is aryl. Insome embodiments, R⁴ is —(CO)R² and R⁵ is heteroaryl. In someembodiments, R⁴ is —(CO)R² and R⁵ is cycloalkyl. In some embodiments,the aryl is optionally substituted phenyl. In some embodiments, the arylis optionally substituted phenyl. In some embodiments, the heteroaryl isa 5- to 14-membered heteroaryl having 1, 2, or 3 heteroatoms selectedfrom the group consisting of N, O, and S. In some embodiments, theoptionally substituted 5- to 14-membered heteroaryl is selected from thegroup consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolizinyl,indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl,benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl.In some embodiments, the heteroaryl is a 5- or 6-membered heteroarylring. In some embodiments, the 5-membered heteroaryl is optionallysubstituted pyrazolyl, imidazolyl, oxazolyl. In some embodiments, the6-membered heteroaryl is optionally substituted pyridinyl, pyrazinyl, orpyridazinyl. In some embodiments, cycloalkyl is optionally substitutedcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In someembodiments, aryl is optionally substituted with one or moresubstituents selected from the group consisting of halogen,C₁₋₆haloalkyl, C₁₋₆alkyl, O-C₁₋₆alkyl, O-C₁₋₆haloalkyl, orC₃₋₆cycloalky. In some embodiments, heteroaryl is optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, C₁₋₆haloalkyl, C₁₋₆alkyl, O-C₁₋₆alkyl, O-C₁₋₆haloalkyl, orC₃₋₆cycloalky.

In some embodiments of Formula (I), R⁴ is —(SO₂)R² and R⁵ is aryl. Insome embodiments, R⁴ is —(SO₂)R² and R⁵ is heteroaryl. In someembodiments, R⁴ is —(SO₂)R² and R⁵ is cycloalkyl. In some embodiments,the aryl is optionally substituted phenyl. In some embodiments, theheteroaryl is a 5- to 14-membered heteroaryl having 1, 2, or 3heteroatoms selected from the group consisting of N, O, and S. In someembodiments, the optionally substituted 5- to 14-membered heteroaryl isselected from the group consisting of pyrazolyl, imidazolyl, oxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolizinyl,indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl,benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl.In some embodiments, the heteroaryl is a 5- or 6-membered heteroarylring. In some embodiments, the 5-membered heteroaryl is optionallysubstituted pyrazolyl, imidazolyl, or oxazolyl. In some embodiments, the6-membered heteroaryl is optionally substituted pyridinyl, pyrirnidinyl,pyrazinyl, or pyridazinyl. In some embodiments, cycloalkyl is optionallysubstituted cyclopropyl, cycloybutyl, cyclopentyl, or cyclohexyl. Insome embodiments, aryl is optionally substituted with one or moresubstituents selected from the group consisting of halogen,C₁₋₆haloalkyl, C₁₋₆alkyl, O-C₁₋₆alkyl, O-C₁₋₆haloalkyl, orC₃₋₆cycloalkyl. In some embodiments, heteroaryl is optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C₁₋₆haloalkyl, C₁₋₆alkyl, O-C₁₋₆alkyl,O-C₁₋₆haloalkyl, or C₃₋₆cycloalkyl. In some embodiments, theC₁₋₆haloalkyl is CF₃, CHF₂, or CH₂F. In some embodiments, theO-C₁₋₆haloalkyl is OCF₃, OCHF₂, or OCH₂F. In some embodiments,cycloalkyl is optionally substituted with halogen, C₁₋₆alkyl, orO-C₁₋₆alkyl.

In some embodiments of Formula (I), R⁴ and R⁵ together with the atom towhich they are attached form a cycloalkyl or heterocyclyl. In someembodiments, R⁴ and R⁵ together with the atom to which they are attachedform a cycloalkyl or heterocyclyl, each of which is optionallysubstituted. In some embodiments, the cycloalkyl or heterocyclyl isoptionally substituted with —NS(O₂)(alkyl)(aryl). In some embodiments,the alkyl is C₁-₅alkyl and the aryl is phenyl optionally substitutedwith one or more halogen atoms. In some embodiments, the heterocyclyl isa 4- to 10-membered heterocyclyl. In some embodiments the heterocyclylis a saturated 4- to 7-membered heterocyclyl.

In some embodiments of Formula (I), n is 0 and R¹ and R⁵ together withthe atom to which they are attached form an optionally substitutedheterocyclyl selected from the group consisting of:

In some embodiments, the optionally substituted heterocyclyl is

In some embodiments, the optionally substituted heterocyclyl is

In some embodiments, the optionally substituted heterocyclyl is

In some embodiments, the optionally substituted heterocyclyl is selectedfrom the group consisting of:

wherein U is O or CH₂. In some embodiments, the optional substituent isan alkyl group. In some embodiments, the optional substituent is an arylgroup.

In some embodiments of Formula (I) R¹ is selected from the groupconsisting of

In some embodiments of Formula (I), R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹

In some embodiments of Formula (I), R^(a) is H, halo, C₁₋₃alkyl, orhaloalkyl. In some embodiments, R¹ is H. In some embodiments, R^(a) isC₁₋₃alkyl. In some embodiments, R^(a) is haloalkyl. In some embodiments,halo is F. In some embodiments, the C₁₋₃alkyl alkyl is methyl, ethyl orisopropyl. In some embodiments, haloalkyl is CF₃, CHF₂, or CH₂F.

In some embodiments of Formula (I), Y is CH and R⁴ and R⁵ are H.

In some embodiments of Formula (I), Y is N, R⁴ is H, and R⁵ is ethyloptionally substituted with —N(S(O₂)alkyl)(aryl) or—N(S(O₂)cycloalkyl)(aryl). In some embodiments, alkyl is C₁₋₅alkyl,cycloalkyl is C₃₋₆cycloalkyl, and aryl is phenyl optionally substitutedwith one or more halogen atoms.

In some embodiments of Formula (I), n is 1, X¹ is O or N, Y is N, R¹ is

R² and R³ are H, R⁴ is H, -C₁₋₅alkyl, —C(O)alkyl, —C(O)cycloalkyl,—(SO₂)NR²R³, —SO₂alkyl, —SO₂haloalkyl and —SO₂cycloalkyl, each of whichis optionally substituted, and R⁵ is aryl, heteroaryl, or cycloalkyl,each of which is optionally substituted.

In some embodiments of Formula (I), n is 1, X¹ is O or N, Y is O, R¹ is

R² and R³ are H, and. R⁵ is aryl, heteroaryl, cycloalkyl, oralkylenecycloalkyl, each of which is optionally substituted.

In some embodiments of Formula (I), is 0, X¹ is O or N, Y is N, R¹ is

and R⁴ and R⁵ taken together with the atom to which they are attachedform a cycloalkyl or heterocyclyl, each of which is optionallysubstituted.

In some embodiments, the present disclosure provides a compound ofFormula (Ia) or a pharmaceutically acceptable salt thereof:

wherein:R¹, R², R³, R⁴, R⁵, R^(a), X¹, n, and Y are as defined above for Formula(I).

In some embodiments of Formula (Ia), R¹ is

n is 1; Y is N; X¹ is S or O; and variables R², R³, R⁴, R⁵, and R^(a)are as defined above for Formula (I).

In some embodiments of Formula (Ia), n is 1, X¹ is S, Y is N, R¹ is

R² and R³ are H, R⁴ is —SO₂alkyl, —SO2haloalkyl, or —SO₂cycloalkyl, eachof which is optionally substituted, R⁵ is heteroaryl, each of which isoptionally substituted, and R^(a) is H or F. In some furtherembodiments, R⁴ is —SO₂C₁₋₅alkyl, —SO₂cyclopropyl, —SO₂CF₃ or —SO₂CHF₂,and the heteroaryl is optionally substituted pyridine or pyrazine. Insome further embodiments, the heteroaryl is optionally substitutedpyridine.

In some embodiments of Formula (Ia), n is 1, X¹ is S, Y is N, R¹ is

R² and R³ are H, R⁴ is —SO₂Me, —SO₂Et, or —SO₂cyclopropyl, each of whichis optionally substituted, R⁵ is pyridine or pyrazine, each of which isoptionally substituted, and R^(a) is H. In some embodiments, R⁵ isoptionally substituted pyridine.

In some embodiments of Formula (Ia), n is 1, X¹ is S, Y is N, R¹ is

R² and R³ are H, R⁴ is —SO₂alkyl or —SO₂cycloalkyl, each of which isoptionally substituted, R⁵

is wherein R^(b) is selected from the group consisting of halogen,-C₁₋₅alkyl, haloalkyl, —OC₁₋₅alkyl, —Ohaloalkyl, —CH₂Ohaloalkyl,cyclopropyl, and CN, and R^(a) is H. In some embodiments, the halogen isF or Cl. In some embodiments, the haloalkyl is CF₃, CHF₂, CH₂CF₃, orCF₂CH₃. In some embodiments, the -C₁₋₅alkyl is methyl.

In some embodiments of Formula (Ia), n is 1, X¹ is S, Y is N, R¹ is

R² and R³ are H, R⁴ is —SO₂Me, —SO₂Et, or —SO₂cyclopropyl, each of whichis optionally substituted, and R⁵ is

wherein R^(b) is selected from the group consisting of halogen,-C₁₋₅alkyl, haloalkyl, —OC₁₋₅alkyl, —Ohaloalkyl, —CH₂Ohaloalkyl,cyclopropyl, or CN, and R^(a) is H. In some embodiments, the halogen isF or Cl. In some embodiments, the haloalkyl is CF₃, CHF₂, CH₂CF₃, orCF₂CH₃. In some embodiments, the -C₁₋₅alkyl is methyl.

In some embodiments of Formula (Ia), n is 1, X¹ is S, Y is N, R¹ is

R² and R³ are H, R⁴ is —SO₂Me, —SO₂Et, or —SO₂cyclopropyl, each of whichis optionally substituted, and R⁵ is

wherein R^(b) is selected from the group consisting of Cl, F, Me,cyclopropyl, CF₃, CHF₂, CH₂CH₃, OCF₃, OCHF₂, OCH2CF2H and CN, and R^(a)is H.

In some embodiments, the present disclosure provides a compound ofFormula (Ib) or a pharmaceutically acceptable salt thereof:

wherein:R¹, R², R³, R⁴, R⁵, R^(a), X¹, n, and Y are as defined above for Formula(I).

In some embodiments of Formulas (I)-(Ib), each optionally substitutedalkyl is independently an optionally substituted C₁₋₆ alkyl. In someembodiments, the C₁₋₆ alkyl is Me or Et.

In some embodiments of Formulas (I)-(Ib), each optionally substitutedhaloalkyl is independently an optionally substituted C₁₋₆ haloalkyl. Insome embodiments, the C₁₋₆ haloalkyl is CF₃, CHF₂, or CH₂F. In someembodiments, the C₁₋₆ haloalkyl is CF₃ or CHF₂.

In some embodiments of Formulas (I)-(Ib), each optionally substitutedcycloalkyl is independently an optionally substituted C₃₋₁₂ cycloalkyl.In some embodiments, the cycloalkyl is a C₃₋₆ cycloalkyl. In someembodiments, the cycloalkyl is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments of Formulas (I)-(Ib), each optionally substitutedheterocyclyl is independently an optionally substituted 3-12 memberedheterocycloalkyl having 1 or 2 heteroatoms independently selected fromN, O, and S. In some embodiments, each optionally substitutedheterocyclyl is independently an optionally substituted 3-6 memberedheterocycloalkyl having 1 or 2 heteroatoms independently selected fromN, O, and S. In further embodiments, the heterocycloalkyl is anoptionally substituted 5-membered or 6-membered heterocycle having 1 or2 heteroatoms independently selected from N, O, and S. In someembodiments, the heterocyclyl is selected from the group consisting ofaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, andthiomorpholinyl.

In some embodiments of Formulas (I)-(Ib), each optionally substitutedaryl is independently a C₆₋₁₂ aryl. In further embodiments, the C₆₋₁₂aryl is an optionally substituted phenyl.

In some embodiments of Formulas (I)-(Ib), each optionally substitutedheteroaryl is independently a 5-12 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S. In someembodiments, each optionally substituted heteroaryl is independently a5-12 membered heteroaryl having 3 heteroatoms independently selectedfrom N, O, and S. In some embodiments, each optionally substitutedheteroaryl is independently a 5-12 membered heteroaryl having 2heteroatoms independently selected from N, O, and S. In someembodiments, each optionally substituted heteroaryl is independently a5-12 membered heteroaryl having 1 heteroatom independently selected fromN, O, and S. In further embodiments, each optionally substitutedheteroaryl is an optionally substituted 5-membered or 6-memberedheteroaryl having 1 heteroatom independently from N, O, and S. In someembodiments, each heteroaryl is independently selected from the groupconsisting of tetrazole, oxadiazole, thiadiazole, imidazole, pyrazole,thiazole, or oxazole, each of which is optionally substituted.

In some embodiments, the compound of Formula (I) is a compound of Table1.

TABLE 1 Compounds of Formula (I) of the Present Disclosure.

In some embodiments, the present disclosure provides a compound ofFormula (Ic) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   R^(a) is H, Me, or F; and    -   R⁴ and R⁵ are as defined above in Formula (I).

In some embodiments of Formula (Ic), R^(a) is H. In some embodiments,R^(a) is F. In some embodiments, R^(a) is Me.

In some embodiments of Formula (Ic), R⁴ is selected from the groupconsisting of alkylenealkoxy, alkyleneheterocyclyl, —S(O)₂alkyl,—S(O)₂cycloalkyl, —S(O)₂alkylenecycloalkyl, —S(O)₂alkyleneheterocyclyl,—S(O)₂N(H)alkyleneheterocyclyl, —C(O)alkyl, —C(O)cycloalkyl,—C(O)alkylenecycloalkyl, —C(O)alkyleneheterocyclyl, and—C(O)N(H)alkyleneheterocyclyl. In some embodiments, R⁴ is selected fromthe group consisting of alkyleneheterocyclyl, —S(O)₂alkyl,—S(O)₂cycloalkyl, —S(O)₂alkyleneheterocyclyl, —C(O)alkyleneheterocyclyl,and —C(O)N(H)alkyleneheterocyclyl. In some embodiments, R⁴ is selectedfrom the group consisting of —S(O)₂alkyl, —S(O)₂cycloalkyl, and—S(O)₂alkyleneheterocyclyl. In some embodiments, R⁴ is —S(O)₂alkyl. Insome embodiments, R⁴ is —S(O)₂cycloalkyl. In some embodiments, R⁴ is—S(O)₂N(H)alkyleneheterocyclyl. In some embodiments, the alkylene is aC₁₋₅ alkylene and the heterocyclyl is an optionally substituted 4- to10-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from thegroup consisting of N, O, and S. In some embodiments, the alkylene is aC₁₋₅ alkylene and the heterocyclyl is an optionally substituted 4- to7-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from thegroup consisting of N, O, and S. In some embodiments, the alkylene is aC₂₋₄ alkylene and the heterocyclyl is an optionally substituted6-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from thegroup consisting of N, O, and S. In some embodiments, the heterocyclylis selected from the group consisting of piperidine, morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, andpiperizine, each of which is optionally substituted. In someembodiments, the optional substituent is selected from the groupconsisting of alkyl, haloalkyl, alkoxy, acyl, sulfonyl, heteroaryl, andheterocyclyl.

In some embodiments of Formula (Ic), R⁵ is selected from the groupconsisting of:

In some embodiments, R⁵ is

In some embodiments, R⁵ is

In some embodiments, R⁵ is

In some embodiments, R⁵ is

In some embodiments, R^(b) is selected from the group consisting ofhalogen, haloalkyl, alkyl, Oalkyl, Ohaloalkyl, alkylene-Ohaloalkyl,cycloalkyl, heterocyclyl aryl, heteroaryl, alkylnitrile, or CN. In someembodiments, R^(b) is selected from the group consisting of halo, alkyl,haloalkyl, alkoxy, haloalkoxy, acyl, sulfonyl, cycloalkyl, heteroaryl,and heterocyclyl. In some embodiments, the haloalkyl is selected fromCF₃, CF₂CH₃, CHF₂, or CH₂F. In some embodiments, the alkyl is a-C₁₋₅alkyl. In some embodiments, -C₁₋₅alkyl is methyl, ethyl, propyl,i-propyl, butyl, or t-butyl. In some embodiments, methyl, ethyl, propyl,i-propyl, butyl, or t-butyl is optionally substituted with OH. In someembodiments, the cycloalkyl is a C₃₋₆cycloalkyl. In some embodiments,the aryl is a phenyl. In some embodiments, the heteroaryl is 5- or6-membered heteroaryl haying 1, 2, or 3 heteroatoms selected from N, O,and S. In some embodiments, the heterocyclyl is a 4- to 7-memberheterocyclyl with 1 or 2 heteroatoms selected from N, O, and S. In someembodiments, the Ohaloalkyl is selected from OCF₃, OCHF₂, or OCH₂F. Insome embodiments, the Oalkyl is O-methyl, O-ethyl, O-propyl, O-i-propyl,O-butyl, or O-t-butyl. In some embodiments, R^(b) is selected from thegroup consisting of F, Cl, —CH₃, —CH₂CH₃, —CF₃, —CHF₂, —CF₂CH₃, —CN,—OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OCHF₂, —OCH₂CF₂H, and cyclopropyl. In someembodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In someembodiments, m is 0. In some embodiments, m is 1. In some embodiments, mis 2.

In some embodiments, R¹ and R⁵ together with the atom to which they areattached form a cycloalkyl or heterocyclyl.

In some embodiments, the present disclosure provides a compound ofFormula (Id) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   U is NR^(d), O, S, S(O), S(O)₂, CH₂, CHF, or CF₂;    -   R^(a) is H, Me, or F;    -   R^(b) is each independently halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —S(O₂)R^(e), cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(e) is each independently F, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —S(O₂)R^(e), heteroaryl, or heterocyclyl, and/or two R^(e)        groups taken together with the carbon atoms to which they are        attached form a bridged or fused C₃₋₇ cycloalkyl, a bridged or        fused 4- to 7-membered heterocyclyl; or a 5- or 6-membered        heteroaryl, each of which is optionally substituted;    -   R^(d) is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or        heteroaryl;    -   R^(e) and R^(e)′ is each independently H, alkyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, —CH₂cycloalkyl,        —CH₂heterocyclyl, —CH₂aryl, or —CH₂heteroaryl;    -   m is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3;    -   q is 0, 1, or 2; and    -   r is 1, 2, 3, or 4.

In some embodiments, the present disclosure provides a compound ofFormula (Ie) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   U is NR^(d), O, S, S(O), S(O)₂, CH₂, CHF, or CF₂;    -   R^(a) is H, Me, or F;    -   R^(b) is each independently halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        sulfonyl, cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(c) is each independently F, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —S(O₂)R^(e), heteroaryl, or heterocyclyl, and/or two R^(e)        groups taken together with the carbon atoms to which they are        attached form a bridged or fused C₃₋₇ cycloalkyl, a bridged or        fused 4- to 6-membered heterocyclyl; or a 5- or 6-membered        heteroaryl, each of which is optionally substituted;    -   R^(d) is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or        heteroaryl;    -   R^(e) and R^(e)′ is each independently H, alkyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, —CH₂cycloalkyl,        —CH₂heterocyclyl, —CH₂aryl, or —CH₂heteroaryl;    -   m is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3;    -   q is 0, 1, or 2; and    -   r is 1, 2, 3, or 4.

In some embodiments, the present disclosure provides a compound ofFormula (If) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   U is NR^(d), O, S, S(O), S(O)₂, CH₂, CHF, or CF₂;    -   R^(a) is H, Me, or F;    -   R^(b) is each independently halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        sulfonyl, cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(c) is each independently F, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —S(O₂)R^(e), heteroaryl, or heterocyclyl, and/or two R^(e)        groups taken together with the carbon atoms to which they are        attached form a bridged or fused C₃₋₇ cycloalkyl, a bridged or        fused 4- to 7-membered heterocyclyl; or a 5- or 6-membered        heteroaryl, each of which is optionally substituted;    -   R^(d) is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or        heteroaryl;    -   R^(e) and R^(e)′ is each independently H, alkyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, —CH₂cycloalkyl,        —CH₂heterocyclyl, —CH₂aryl, or —CH₂heteroaryl;    -   m is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3;    -   q is 0, 1, or 2; and    -   r is 1, 2, 3, or 4.

In some embodiments, the present disclosure provides a compound ofFormula (Ig) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   U is NR^(d), O, S, S(O), S(O)₂, CH₂, CHF, or CF₂;    -   R^(a) is H, Me, or F;    -   R^(b) is each independently halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        sulfonyl, cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(c) is each independently F, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —S(O₂)R^(e), heteroaryl, or heterocyclyl, and/or two R^(e)        groups taken together with the carbon atoms to which they are        attached form a bridged or fused C₃₋₇ cycloalkyl, a bridged or        fused 4- to 7-membered heterocyclyl; or a 5- or 6-membered        heteroaryl, each of which is optionally substituted;    -   R^(d) is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or        heteroaryl;    -   R^(e) and R^(e)′ is each independently H, alkyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, —CH₂cycloalkyl,        —CH₂heterocyclyl, —CH₂aryl, or —CH₂heteroaryl;    -   m is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3;    -   q is 0, 1, or 2; and    -   r is 1, 2, 3, or 4.

In some embodiments, the present disclosure provides a compound ofFormula (Id-1), (Ie-1), (If-1), or (Ig-1) or a pharmaceuticallyacceptable salt or stereoisomer thereof:

wherein:

-   -   U, R^(a), R^(b), m, and r are as defined above in Formulas (Id),        (Ie), (If), and (Ig); and    -   V is O or NR^(d).

In some embodiments, the present disclosure provides a compound ofFormula (Id-2), (Id-3), (Id-4), or a pharmaceutically acceptable salt orstereoisomer thereof:

wherein:

-   -   U, R^(a), R^(b), m, and r are as defined above in Formulas (Id),        (Ie), (If), and (Ig); and    -   V is O or NR^(d).

In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), U isNR^(d), O, or S and V is O. In some embodiments, U is N, O, or S and Vis NR^(d). In some embodiments, U is NR^(d) and V is NR^(d). In someembodiments, U is O and V is NR^(d). In some embodiments, U is S and Vis NR^(d). In some embodiments, U is NR^(d) and V is O. In someembodiments, U is O and V is O. In some embodiments, U is S and V is O.

In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), U is O, S,S(O)₂, CH₂, or NR^(d). In some embodiments, U is O, S, CH₂, or NR^(d).In some embodiments, U is O, S, or NR^(d). In some embodiments, U is Oor CH₂. In some embodiments, U is O. In some embodiments, U is S. Insome embodiments, U is NR^(d). In some embodiments, U is S(O)₂.

In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), R^(a) is H.In some embodiments, R^(a) is F. In some embodiments, R^(d) is Me.

In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), R^(b) ishalo, alkyl, haloalkyl, alkyl, haloalkoxy, cycloalkyl, heterocyclyl,heteroaryl, or nitrile. In some embodiments, R^(b) is halo, alkyl,haloalkyl, alkyl, haloalkoxy, cycloalkyl, or nitrite. In someembodiments, the haloalkyl is selected from CF₃, CF₂CH₃, CHF₂, or CH₂F.In some embodiments, the alkyl is a -C₁₋₅alkyl. In some embodiments,-C₁₋₅alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. Insome embodiments, the cycloalkyl is a C₃₋₆cycloalkyl. In someembodiments, the heteroaryl is 5- or 6-membered heteroaryl having 1, 2,or 3 heteroatoms selected from N, O, and S. In some embodiments, theheterocyclyl is a 4- to 7-member heterocyclyl with 1 or 2 heteroatomsselected from N, O, and S. In some embodiments, the haloalkoxy isselected from OCF₃, OCHF₂, or OCH₂F. In some embodiments, the alkoxy isO-methyl, O-ethyl, O-propyl, O-i-propyl, O-butyl, or O-t-butyl. In someembodiments, R^(b) is —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′).

In some embodiments of Formulas (Id)-(Ig), R^(c) is F, C₁₋₅ alkyl,haloalkyl, C₁₋₅ alkoxy, haloalkoxy, acyl, sulfonyl, 5- or 6-memberedheteroaryl, or C₃₋₆ heterocyclyl. In some embodiments, R^(c) is—C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′). In some embodiments, twoR^(c) groups taken together with the carbon atoms to which they areattached form a bridged or fused C₃₋₇ cycloalkyl, a bridged or fused 5-or 6-membered heterocyclyl, or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted. In some embodiments, two R^(c) groupstaken together with the carbon atoms to which they are attached form anoptionally substituted bridged or fused C₃₋₇ cycloalkyl. In someembodiments, two R^(c) groups taken together with the carbon atoms towhich they are attached form an optionally substituted bridged or fused5- or 6-membered heterocyclyl. In some embodiments, two ^(c) groupstaken together with the carbon atoms to which they are attached form analkoxy or aminoalkyl bridge. In some embodiments, the optionalsubstituent is one or more R^(b), as defined above. In some embodiments,the optional subsitutuent is selected from the group consisting of F,C₁₋₅ alkyl, C₁₋₅ alkoxy, CF₃, CF₂H, CFH₂, —OCF₃, —OCF₂H, —OCFH₂,—C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′), and —SO₂R^(e). In someembodiments, the optional subsitutuent is selected from the groupconsisting of F, C₁₋₅ alkyl, C₁₋₅ alkoxy, CF₃, CF₂H, CFH₂, —OCF₃,—OCF₂H, and —OCFH₂. In some embodiments, the optional subsitutuent is For C₁₋₅ alkyl. In some embodiments, the optional subsitutuent is F. Insome embodiments, the optional subsitutuent is C₁₋₅ alkyl. In someembodiments, the C₁₋₅ alkyl is methyl. In some embodiments, the C₁₋₅alkyl is ethyl. In some embodiments, the C₁₋₅ alkyl is propyl. In someembodiments, the C₁₋₅ alkyl is isopropyl.

In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), R^(e) andR^(e)′ is each independently H, alkyl, cycloalkyl, or —CH₂cycloalkyl. Insome embodiments, the alkyl is a -C₁₋₅alkyl. In some embodiments,-C₁₋₅alkyl is methyl, ethyl, propyl, i-propyl, butyl, or t-butyl. Insome embodiments, the cycloalkyl is a C₃₋₆cycloalkyl. In someembodiments, the cycloalkyl is cyclopropyl. In some embodiments, R^(e)and R^(e)′ are H.

In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), m is 0, 1,or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. Insome embodiments, m is 1. In some embodiments, m is 2.

In some embodiments of Formulas (Id)-(Ig), p is 0, 1, or 2. In someembodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In someembodiments, p is 0. In some embodiments, p is 1. In sonic embodiments,p is 2.

In some embodiments of Formulas (Id)-(Ig) and (Id-1)-(Ig-1), r is 1, 2,or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 2 or3. In some embodiments, r is 1. In some embodiments, r is 2. In someembodiments, r is 3. In some embodiments, r is 4.

In some embodiments of Formulas (Id)-(Ig), q is 0 or 1. In someembodiments, q is 0. In some embodiments, q is 1. In some embodiments, qis 2.

In some embodiments of Formulas (Id)-(Ig), r is 1 and p is 1. In someembodiments, r is 2 and p is 1. In some embodiments, r is 3 and p is 1.

In some embodiments, the present disclosure provides a compound ofFormula (Ih) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   U is NR^(d), O, S, S(O), S(O)₂, CH₂, CHF, or CF₂;    -   X¹, X², X³, and X⁴ is each independently CH or N;    -   R^(a) is H, Me, or F;    -   R^(b) is each independently halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —SO₂R^(e), cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(c) is each independently F, alkyl, haloalkyl, alkoxy, or        haloalkoxy, and/or two R^(c) groups taken together with the        atoms to which they are attached form an optionally substituted        C₃₋₇ cycloalkyl;    -   R^(d) is H, alkyl, acyl, sulfonyl, cycloalkyl, aryl, or        heteroaryl;    -   R^(e) and R^(e)′ is each independently H, alkyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, —CH₂cycloalkyl,        —CH₂heterocyclyl, —CH₂aryl, or —CH₂heteroaryl;    -   m is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound ofFormula (Ii) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   U is NR^(d), O, S, S(O), S(O)₂, CH₂, CHF, or CF₂;    -   X¹, X², X³, and X⁴ is each independently CH or N;    -   R^(a) is H, Me, or F;    -   R^(b) is each independently halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —SO₂R^(e), cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(c) is each independently F, alkyl, haloalkyl, alkoxy, or        haloalkoxy, and/or two R^(c) groups taken together with the        atoms to which they are attached form an optionally substituted        C₃₋₇ cycloalkyl;    -   R^(d) is H, alkyl, —C(O)R^(e), sulfonyl, cycloalkyl, aryl, or        heteroaryl;    -   R^(e) and R^(e)′ is each independently H, alkyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, —CH₂cycloalkyl,        —CH₂heterocyclyl, —CH₂aryl, or —CH₂heteroaryl;    -   m is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound ofFormula (Ij) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   U is NR^(d), O, S, S(O), S(O)₂, CH₂, CHF, or CF₂;    -   X¹, X², X³, and X⁴ is each independently CH or N;    -   R^(a) is H, Me, or F;    -   R^(b) is each independently halo, alkyl, haloalkyl, alkoxy,        haloalkoxy, —C(O)R^(e), —C(O)OR^(e), —C(O)N(R^(e))(R^(e)′),        —SO₂R^(e), cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(c) is each independently F, alkyl, haloalkyl, alkoxy, or        haloalkoxy, and/or two R^(c) groups taken together with the        atoms to which they are attached form an optionally substituted        C₃₋₇ cycloalkyl;    -   R^(d) is H, alkyl, —C(O)R^(e), sulfonyl, cycloalkyl, aryl, or        heteroaryl;    -   R^(e) and R^(e)′ is each independently H, alkyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, —CH₂cycloalkyl,        —CH₂heterocyclyl, —CH₂aryl, or —CH₂heteroaryl;    -   m is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2.

In some embodiments of Formulas (Ih)-(Ij), NR^(d), O, S, S(O)₂, or CH₂.In some embodiments, U is NR^(d), O, S, or CH₂. In some embodiments, Uis O or CH₂. In some embodiments, U is O. In some embodiments, U is CH₂.In some embodiments, U is S. In some embodiments, U is S(O)₂. In someembodiments, U is NR^(d).

In some embodiments of Formulas (Ih)-(Ij), each of X¹, X², X³, and X⁴ isCH. In some embodiments, one of X¹, X², X³, and X⁴ is N. In someembodiments, two of X¹, X², X³, and X⁴ are N. In some embodiments, X¹ isN and each of X², X³, and X⁴ is CH. In some embodiments, X² is N andeach of X¹, X³, and X⁴ is CH. In some embodiments, X¹ is N and each ofX¹, X², and X⁴ is CH. In some embodiments, X⁴ is N and each of X¹, X²,and X³ is CH.

In some embodiments of Formulas (Ih)-(Ij), U is CH₂ and one of X¹, X²,X³, and X⁴ is N. In some embodiments, U is CH₂, X¹ is N and each of X²,X³, and X⁴ is CH. In some embodiments, U is CH₂, X² is N and each of X¹,X³, and X⁴ is CH. In some embodiments, U is CH₂, X³ is N and each of X¹,X², and X⁴ is CH. In some embodiments, U is CH₂, X⁴ is N and each of X¹,X², and X³ is CH. In some embodiments, p is 0. In some embodiments, p is1.

In some embodiments of Formulas (Ih)-(Ij), U is O and one of X¹, X², X³,and X⁴ is N. In some embodiments, U is O, X¹ is N and each of X², X³,and X⁴ is CH. In some embodiments, U is O, X² is N and each of X¹, X³,and X⁴ is CH. In some embodiments, U is O, X³ is N and each of X¹, X²,and X⁴ is CH. In some embodiments, U is O, X⁴ is N and each of X¹, X²,and X³ is CH.

In some embodiments of Formulas (Ih)-(Ij), R^(a) is H. In someembodiments. R^(a) is F. In some embodiments, R^(a) is Me.

In some embodiments of Formulas (Ih)-(Ij), R^(b) is halo, alkyl,haloalkyl, alkyl, haloalkoxy, cycloalkyl, heterocyclyl, heteroaryl, ornitrile. In some embodiments, R^(b) is halo, alkyl, haloalkyl, alkyl,haloalkoxy, cycloalkyl, or nitrile. In some embodiments, the haloalkylis selected from CF₃, CF₂CH₃, CHF₂, or CH₂F. In some embodiments, thealkyl is a -C₁₋₅alkyl. In some embodiments, -C₁₋₅alkyl is methyl, ethyl,propyl, i-propyl, butyl, or t-butyl. In some embodiments, the cycloalkylis a C₃₋₆cycloalkyl. In some embodiments, the heteroaryl is 5- or6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O,and S. In some embodiments, the heterocyclyl is a 4- to 7-memberheterocyclyl with 1 or 2 heteroatoms selected from N, O, and S. In someembodiments, the haloalkoxy is selected from OCF₃, OCHF₂, or OCH₂F. Insome embodiments, the alkoxy is O-methyl, O-ethyl, O-propyl, O-i-propyl,O-butyl, or O-t-butyl.

In some embodiments of Formulas (Ih)-(Ij), R^(c) is F, C₁₋₅ alkyl,haloalkyl, C₁₋₅ alkoxy, haloalkoxy, acyl, sulfonyl, 5- or 6-memberedheteroaryl, or C₃₋₆ heterocyclyl. In some embodiments, R^(c) is F, C₁₋₅alkyl, haloalkyl, C₁₋₅ alkoxy, or haloalkoxy. In some embodiments, R^(c)is F or C₁₋₅ alkyl. In some embodiments, R^(c) is F or methyl. In someembodiments, R^(c) is F. In some embodiments, R^(c) is methyl. In someembodiments, the two R^(c) groups are attached to the same carbon atom,which can also be referred to as germinal substitution. In someembodiments, two R^(c) groups taken together with the atoms to whichthey are attached form an optionally substituted C₃₋₆ cycloalkyl. Insome embodiments, two R^(c) groups taken together with the atoms towhich they are attached form an optionally substituted cyclopropyl. Insome embodiments, the optional substituent is one or more R^(b), asdefined above. In some embodiments, the optional subsitutuent isselected from the group consisting of F, C₁₋₅ alkyl, C₁₋₅ alkoxy, CF₃,CF₂H, CFH₂, —OCF₃, —OCF₂H, —OCFH₂, —C(O)R^(e), —C(O)OR^(e),—C(O)N(R^(e))(R^(e)′), and —SO₂R^(e). In some embodiments, the optionalsubsitutuent is selected from the group consisting of F, C₁₋₅ alkyl,C₁₋₅ alkoxy, CF₃, CF₂H, CFH₂, —OCF₃, —OCF₂H, and -—OCFH₂. In someembodiments, the optional subsitutuent is F or C₁₋₅ alkyl. In someembodiments, the optional subsitutuent is F. In some embodiments, theoptional subsitutuent is C₁₋₅ alkyl. In some embodiments, the C₁₋₅ alkylis methyl. In some embodiments, the C₁₋₅ alkyl is ethyl. In someembodiments, the C₁₋₅ alkyl is propyl. In some embodiments, the C₁₋₅alkyl is isopropyl. In some embodiments, two optional substituents areattached to the same carbon, which is also referred to as germinalsubstitution.

In some embodiments of Formulas (Ih)-(Ij), when U is NR^(d), an R^(d)and R^(c) taken together with the atoms to which they are attached forma 5- to 7-membered heterocyclyl. In some embodiments, an R^(d) and R^(c)taken together with the atoms to which they are attached form a6-membered heterocyclyl. In some embodiments, the heterocyclyl comprises1 or 2 heteroatoms selected from N, O, and S.

In some embodiments, the present disclosure provides a compound ofFormula (Ih-1), Formula (Ii-1), or Formula (Ij-1):

wherein R^(a), R^(b), R^(c), X¹, X², X³, X⁴, U, and m are as definedabove in Formula (Ih), Formula (Ii), and Formula (Ij).

In some embodiments of Formula (I-h-1), Formula (Ii-1), and Formula(Ij-1), each R^(c) is F. In some embodiments, each R^(c) is Me. In someembodiments, two ^(c) groups taken together with the carbon atoms towhich they are attached form an optionally substituted C₃₋₆ cycloalkyl.In some embodiments, two R^(c) groups taken together with the carbonatoms to which they are attached form a cyclopropyl or cyclobutyl, eachof which is optionally substituted. In some embodiments, two R^(c)groups taken together with the carbon atoms to which they are attachedform an optionally substituted cyclopropyl. In some embodiments, theoptional subsitutuent is F or C₁₋₅ alkyl. In some embodiments, theoptional subsitutuent is F. In some embodiments, the optionalsubsitutuent is C₁₋₅ alkyl. In some embodiments, the C₁₋₅ alkyl ismethyl. In some embodiments, the C₁₋₅ alkyl is ethyl. In someembodiments, the C₁₋₅ alkyl is propyl. In some embodiments, the C₁₋₅alkyl is isopropyl. In some embodiments, two optional substituents areattached to the same carbon, which is also referred to as germinalsubstitution.

In some embodiments, R^(d) is H, alkyl, or cycloalkyl. In someembodiments, R^(d) is H. In some embodiments, R^(d) is alkyl. In someembodiments, R^(d) is cycloalkyl. In some embodiments, alkyl is methyl,ethyl, propyl, isopropyl, or t-butyl. In some embodiments, thecycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl.

In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1.In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2.

In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1.In some embodiments, p is 1 or 2. In some embodiments, p is 0. In someembodiments, p is 1. In some embodiments, p is 2.

In some embodiments, q is 0 or 1. In some embodiments, q is 0. In someembodiments, q is 1. In some embodiments, q is 2.

In some embodiments, the present disclosure provides a compound ofFormula (Ik) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   R^(b) is haloalkoxy; and    -   R⁴ is alkyl.

In some embodiments, the present disclosure provides a compound ofFormula (Ik-1) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   R^(b) is haloalkoxy; and    -   R⁴ is alkyl.

In some embodiments, the present disclosure provides a compound ofFormula (Ik-2) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   R^(b) is haloalkoxy; and    -   R⁴ is alkyl.

In some embodiments, the present disclosure provides a compound ofFormula (Ik-3) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   R^(b) is haloalkoxy; and    -   R⁴ is alkyl.

In some embodiments of Formulas (Ik)-(Ik-3), R^(b) is H, —OCF₃, —OCHF₂,—OCH₂F, —OCH₂CF₃. In some embodiments, R^(b) is H, or —OCHF₂. In someembodiments, R^(b) is H or —OCH₂F. In some embodiments, R^(b) is H or—OCF₂. In some embodiments, R^(b) is H or —CHF₂. In some embodiments,R^(b) is —OCF₃. In some embodiments, R^(b) is —OCHF₂. In someembodiments, R^(b) is —OCH₂F.

In some embodiments of Formulas (Ik)-(Ik-3), R⁴ is a C₁₋₅ alkyl. In someembodiments, R⁴ is methyl, ethyl, or propyl. In some embodiments, R⁴ ismethyl or ethyl. In some embodiments, R⁴ is methyl. In some embodiments,R⁴ is ethyl. In some embodiments, R⁴ is propyl.

In some embodiments of Formulas (Ik)-(Ik-3), R^(b) is H, —OCF₃, —OCHF₂or —OCH₂F and R⁴ is a C₁₋₅ alkyl. In some embodiments, R^(b) is H or—OCHF₂ and R⁴ is a C₁₋₅ alkyl. In some embodiments, R^(b) is H or —OCH₂Fand R⁴ is a C₁₋₅ alkyl. In some embodiments, R^(b) is H or —OCF₃ and R⁴is a C₁₋₅ alkyl. In some embodiments, R^(b) is H or —OCH₂F and R⁴ is aC₁₋₅ alkyl. In some embodiments, the C₁₋₅ alkyl is methyl, ethyl, orpropyl. In some embodiments, the C₁₋₅ alkyl is methyl. In someembodiments, the C₁₋₅ alkyl is ethyl. In some embodiments, the C₁₋₅alkyl is propyl.

Compounds of Formula (IL)

In one aspect, the present disclosure provides a compound of Formula(II) or pharmaceutically acceptable salt thereof:

whereinR¹ is selected from the group consisting of:

R^(a) is selected from the group consisting of H, halo, C₁₋₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² is selected from the group consisting of H, aryl, heteroaryl,cycloalkyl, heterocyclyl, alkyl, haloalkyl, alkoxy, —(CH₂)_(m)aryl,—(CH₂)_(m)N(R³)aryl, —(CH₂)_(m)Oaryl, —(CH₂)_(m)(SO₂)aryl,—(CH₂)_(m)heteroaryl, —(CH₂)_(m)N(R³)heteroaryl, —(CH₂)_(m)Oheteroaryl,—(CH₂)_(m)cycloalkyl, —(CH₂)_(m)heterocyclyl, —(CH₂)_(m)(COOH),—(CH₂)_(m)(COOR³), —(CH₂)_(m)(CONR³R⁴), —(CH₂)_(m)(NR³SO₂NR³R⁴), and—(CH₂)_(m)(SO₂R³), each of which is optionally substituted, wherein m isselected from 1, 2, or 3;R³ and R⁴ are independently selected from the group consisting of H,aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyl, each of which isoptionally substituted or R³ and R⁴ together with the atom to which theyare attached form an optionally substituted heterocyclyl; andX¹, X² and X³ are independently selected from C and N, with the provisothat X¹ and X² cannot both be N.

In some embodiments of Formula (II), X¹, X² and X³ are C. In someembodiments, X¹ is N and X² and X³ are C. In some embodiments, X¹ and X³are C and X² is N.

In some embodiments of Formula (II), R^(a) is H, halo, C₁₋₃alkyl, orhaloalkyl. In some embodiments, R^(a) is H. In some embodiments, R^(a)is C₁₋₃alkyl. In some embodiments, R^(a) is haloalkyl. In someembodiments, halo is F. In some embodiments, the C₁₋₃alkyl alkyl ismethyl, ethyl or isopropyl. In some embodiments, haloalkyl is CF₃, CHF₂,or CH₂F.

In some embodiments of Formula (II), R² is —(CH₂)_(m)cycloalkyl,—(CH₂)_(m)heterocyclyl, —(CH₂)_(m)aryl, —(CH₂)_(m)N(R³)aryl,—(CH₂)_(m)Oaryl, —(CH₂)_(m)heteroaryl, —(CH₂)_(m)N(R³)heteroaryl, or—(CH₂)_(m)Oheteroaryl, each of which is optionally substituted, whereinm is 1, 2, or 3.

In some embodiments of Formula (II), R² is optionally substituted—(CH₂)_(m)cycloalkyl, wherein m is 1, 2, or 3. In some embodiments,cycloalkyl is a C₃₋₆cycloalkyl. In some embodiments, the cycloalkyl iscyclopropyl. In some embodiments, the cycloalkyl is cyclobutyl. In someembodiments, the cycloalkyl is cyclopentyl. In some embodiments, thecycloalkyl is cyclohexyl.

In some embodiments, R² is heterocyclyl or —(CH₂)_(m)heterocyclyl, eachof which is optionally substituted, wherein m is 1, 2, or 3. In someembodiments, heterocyclyl is selected from the group consisting ofazetidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl,thiomorpholine-1,1-dioxide, tetrahydropyranyl, piperidinyl, orpiperizinyl, each of which is optionally substituted. In someembodiments, the heterocyclyl is 2-oxa-5-azabicyclo[2.2.1]heptane,8-azabicyclo[3.2.1]ooctane, or 9-azabicyclo[3.3.1]nonane.

In some embodiments, R² is —(CH₂)_(m)aryl, —(CH₂)_(m)N(R³)aryl, or—(CH₂)_(m)Oaryl, each of which is optionally substituted., wherein m is1, 2, or 3. In some embodiments, aryl is an optionally substitutedphenyl or naphthalenyl. In some embodiments, aryl is an optionallysubstituted phenyl.

In some embodiments, R² is —(CH₂)_(m)heteroaryl, —(CH₂)_(m)N(R³)aryl, or—(CH₂)_(m)Oaryl, each of which is optionally substituted, wherein m is1, 2, or 3. In some embodiments, heteroaryl is an optionally substituted5- to 14-membered heteroaryl. In some embodiments, heteroaryl is anoptionally substituted 5- to 14-membered heteroaryl having 1, 2, or 3heteroatoms selected from the group consisting of N, O, and S. In someembodiments, the optionally substituted 5- to 14-membered heteroaryl isselected from the group consisting of pyrazolyl, imidazolyl, oxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, quinoxalinyl, cinnolinyl, indolizinyl, azaindolizinyl,indolyl, azaindolyl, benzoxazolyl, benzthiazolyl, benzfuranyl,benzthiophenyl, imidazopyridinyl, imidazopyrazinyl, and benzimidazolyl.In some embodiments, the optionally substituted 5- to 14-memberedheteroaryl is selected from the group consisting of pyrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl,imidazopyridinyl, and imidazopyrazinyl. In some embodiments, theheteroaryl is quinolinyl, pyridinyl, pyrimidinyl, oxazolyl, imidazolyl,pyrazolyl, or pyrazinyl.

In some embodiments of Formula (II), R² is selected from the groupconsisting of H, CH₃, CH₂-C₆H₅, CH₂CH₂-C₆H₅, CH₂(COOt-Bu), CH₂(COOH),CH₂(CO—N-morpholine), and CH₂(CO—N-pyrrolidine). In some embodiments ofFormula (II), R² is optionally substituted with one or more halogenatoms and/or one or more C₁₋₅alkyl groups.

In some embodiments of Formula (II), R² is unsubstituted C₁₋₆ alkyl. Insome embodiments, R² is substituted C₁₋₆ alkyl. In some embodiments, thesubstituted C₁₋₆ alkyl is 2,2-dimethylpropylnitrile (i.e.,—CH₂C(CH₃)₂—CN).

In some embodiments of Formula (II), R² is —C(H)(CH₃)-C₆H₅. In someembodiments R² is alkylene-O-alkyl, or alkylene-O-aryl. In someembodiments, R² is alkylene-CN. In some embodiments of Formula (II), R²is —(CH₂)_(m)heteroaryl. In some embodiments of Formula (II), R² is—(CH₂)_(m)aryl. In some embodiments, R² is optionally substituted—(CH₂)_(m)cycloalkyl. In some embodiments, R² is optionally substitutedcycloalkyl. In some embodiments, R² is —(CH₂)_(m)(COOR³). In someembodiments, R² is —(CH₂)_(m)(CONR³R⁴). In some embodiments, m isselected from 1, 2, or 3. In some embodiments of Formula (II), R² isoptionally substituted with one or more halogen atoms and/or one or moreC₁₋₅alkyl groups. In some embodiments, R² is optionally substituted—(CH₂)_(m)heterocyclyl.

In some embodiments of Formula (II), the R² groups defined above areoptionally substituted on an available carbon or heteroatom by one ormore substituents independently selected from the group consisting ofoxo, halo, C₁₋₆alkyl, haloalkyl, Ohaloalkyl, C₃₋₆cycloalkyl, 4- to6-membered heteroaryl, phenyl, SO₂alkyl, SO₂aryl, C(O)alkyl, C(O)aryl,CO₂alkyl, CO₂aryl, and CN.

In some embodiments of Formula (II), alkyl, aryl, cycloalkyl, orheterocyclyl are each optionally substituted on an available carbon byone or more substituents independently selected from the groupconsisting of halo, —OR⁷, alkyl, phenyl, heteroaryl, CN, COOR⁷, C(O)R⁷,SO₂R⁷, and CONR⁷R⁸, wherein R⁷, and R⁸ are independently for eachoccurrence selected from the group consisting of H, alkyl and aryl,wherein the alkyl and aryl are optionally substituted with one or morehalogens and/or one or more alkyl groups.

In some embodiments, m is 1. In some embodiments, m is 2. In someembodiments, m is 3. In some embodiments, in is 1 or 2. In someembodiments of Formula (II), R³ and R⁴ are independently selected fromthe group consisting of H, aryl, heteroaryl, cycloalkyl, heterocyclyl,and alkyl, each of which is optionally substituted. In some embodiments,the aryl, heteroaryl, cycloalkyl, heterocyclyl, and alkyl are optionallysubstituted with one or more halogen atoms and/or one or more C₁₋₅alkylgroups.

In some embodiments of Formula (II), R³ and R⁴ together with the atom towhich they are attached form a heterocyclyl. In some embodiments theheterocyclyl is optionally substituted with one or more C₁₋₅alkylgroups.

In some embodiments of Formula (II), R¹ is

In some embodiments, R¹ is

In some embodiments of Formula (II), R¹ is

X¹, X² and X³ are C; R² is selected from the group consisting of aryl,C-linked heteroaryl, cycloalkyl, C-linked heterocyclyl, alkyl,haloalkyl, —(CH₂)_(m)aryl, —(CH₂)_(m)heteroaryl, —(CH₂)_(m)cycloalkyl,—(CH₂)_(m)heterocyclyl, —(CH₂)_(m)(COOH), —(CH₂)_(m)(COOR³),—(CH₂)_(m)(CONR³R⁴), —(CH₂)_(m)(NR³SO₂NR³R⁴), and —(CH₂)_(m)(SO₂R³),each of which is optionally substituted; wherein m is selected from 1,2, or 3; and variables R^(a), R³ and R⁴ are as defined above for Formula(II).

In some embodiments of Formula (II), R¹ is

X¹, X² and X³ are C; R² is selected from the group consisting of aryl,C-linked heteroaryl, cycloalkyl, C-linked heterocyclyl, alkyl,haloalkyl, —(CH₂)_(m)aryl, —(CH₂)_(m)(NR³)aryl, —(CH₂)_(m)Oaryl,—(CH₂)_(m)heteroaryl, —(CH₂)_(m)(NR³)heteroaryl, —(CH₂)_(m)Oheteroaryl,—(CH₂)_(m)cycloalkyl, —(CH₂)_(m)heterocyclyl, —(CH₂)_(m)(COOH),—(CH₂)_(m)(COOR³), —(CH₂)_(m)(CONR³R⁴), —(CH₂)_(m)(NR³SO₂NR³R⁴), and—(CH₂)_(m)(SO₂R³), each of which is optionally substituted; wherein m isselected from 1, 2, or 3; and variables R^(a), R³ and R⁴ are as definedabove for Formula (II).

In some embodiments of Formula (II), R¹ is

X¹ is N, X² and X³ are C; R² is selected from the group consisting ofaryl, C-linked heteroaryl, cycloalkyl, C-linked heterocyclyl, alkyl,haloalkyl, —(CH₂)_(m)aryl, —(CH₂)_(m)(NR³)aryl, —(CH₂)_(m)Oaryl,—(CH₂)_(m)heteroaryl, —(CH₂)_(m)(NR³)heteroaryl, —(CH₂)_(m)Oheteroaryl,—(CH₂)_(m)cycloalkyl, —(CH₂)_(m)heterocyclyl, —(CH₂)_(m)(COOH),—(CH₂)_(m)(COOR³), —(CH₂)_(m)(CONR³R⁴), —(CH₂)_(m)(NR³SO₂NR³R⁴), and—(CH₂)_(m)(SO₂R³), each of which is optionally substituted; wherein m isselected from 1, 2, or 3; and variables R^(a), R³ and R⁴ are as definedabove for Formula (II).

In some embodiments of Formula (II), each optionally substituted alkylis independently an optionally substituted C₁₋₆ alkyl. In furtherembodiments, the C₁₋₆ alkyl is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amyl,and isoamyl. In further embodiments, the C₁₋₆ alkyl is selected from thegroup consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, amyl, and isoamyl. In some embodiments, the C₁₋₆alkyl is Me or Et.

In some embodiments of Formula (II), each optionally substitutedcycloalkyl is independently an optionally substituted C₃₋₁₂ cycloalkyl.In some embodiments, the cycloalkyl is a C₃₋₆ cycloalkyl. In someembodiments, the cycloalkyl is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments of Formula (II), each optionally substitutedheterocyclyl is independently an optionally substituted 3-12 memberedheterocycloalkyl having 1 or 2 heteroatoms independently selected fromN, O, and S. In some embodiments, each optionally substitutedheterocyclyl is independently an optionally substituted 3-6 memberedheterocycloalkyl having 1 or 2 heteroatoms independently selected fromN, O, and S. In further embodiments, the heterocycloalkyl is anoptionally substituted 5-membered or 6-membered heterocycle having 1 or2 heteroatoms independently selected from N, O, and S. In someembodiments, the heterocyclyl is a saturated 4-7 membered heterocyclylcontaining one or two heteroatoms independently selected from the groupconsisting of N, NR⁶O and SO₂. In some embodiments, R⁶ is selected fromthe group consisting of C₁-C₆ alkyl, —COO-alkyl, and C(O)-alkyl. In someembodiments, the heterocyclyl is selected from the group consisting ofaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, andthiomorpholinyl.

In some embodiments of Formula (II), each optionally substituted aryl isindependently a C₆₋₁₂ aryl. In further embodiments, the C₆₋₁₂ aryl is anoptionally substituted phenyl.

In some embodiments of Formula (II), each optionally substitutedheteroaryl is independently a 5-12 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S. In someembodiments, each optionally substituted heteroaryl is independently a5-12 membered heteroaryl having 3 heteroatoms independently selectedfrom N, O, and S. In some embodiments, each optionally substitutedheteroaryl is independently a 5-12 membered heteroaryl having 2heteroatoms independently selected from N, O, and S. In someembodiments, each optionally substituted heteroaryl is independently a5-12 membered heteroaryl having 1 heteroatom independently selected fromN, O, and S. In further embodiments, each optionally substitutedheteroaryl is an optionally substituted 5-membered or 6-memberedheteroaryl having 1 heteroatom independently from N, O, and S. Infurther embodiments, each optionally substituted heteroaryl is anoptionally substituted 5-membered or 6-membered heteroaryl having 1 or 2N atoms. In some embodiments, each heteroaryl is independently selectedfrom the group consisting of tetrazole, oxadiazole, thiadiazole,imidazole, pyrazole, thiazole, or oxazole, each of which is optionallysubstituted. In some embodiments, the heteroaryl is tetrazole. In someembodiments, the heteroaryl is oxadiazole.

In some embodiments, the compound of Formula (I) is a compound of Table2.

TABLE 2 Compounds of Formula (II) of the Present Disclosure.

Compounds of Formulas (III)

In another aspect, the present disclosure provides a compound of Formula(III) or pharmaceutically acceptable salt thereof:

whereinR¹ is selected from the group consisting of:

  and

;R^(a) is selected from the group consisting of halo, C₁₋₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² and R³ are independently selected from the group consisting of H,halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl, orR² and R³ together with the atom to which they are attached form acycloalkyl or heterocyclyl;

R⁴ and R⁵ are selected from the group consisting of H, —(SO₂)R²,—(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl, arylheteroaryl, heteroaryl,cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, each of which isoptionally substituted or R⁴ and R⁵ together with the atom to which theyare attached form a cycloalkyl or heterocyclyl;

X¹, X², and X³ are selected from the group consisting of: (1) X¹ isCR^(a), X² is N, and X³ is CR^(a); (2) X¹ is N, X² is CR^(a), and X³ isCR^(a); (3) X¹ is CR^(a), X² is CR^(a), and X³ is N; (4) X¹ is N, X² isCR^(a), and X³ is (5) X¹ is CR^(a), X² is N, and X³ is N; and (6) X¹ isN, X² is N, and X³ is CR^(a);Y is selected from the group consisting of CR², O, N, S, SO, and SO₂,wherein when Y is O, S, SO, or SO₂, R⁵ is not present and when R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, Y is CR² or N; andn is 1 or 2.

In some embodiments, n is 1. In some embodiments n is 2.

In some embodiments of Formula (III), wherein X¹ is CR^(a), X² is N; andX³ is CR^(a). In some embodiments, X¹ is N, X² is CR^(a); and X³ isCR^(a). In some embodiments, R^(a) is H.

In some embodiments of Formula (III), R² and R³ are H.

In some embodiments of Formula (III), Y is —CR² and R² is H.

In some embodiments of Formula (III), Y is N. In some embodiments ofFormula (III), R⁴ is —(SO₂)R² and R⁵ is aryl. In some embodiments, R⁴ is—(SO₂)R² and R⁵ is heteroaryl. In some embodiments, R⁴ is —(SO₂)R² andR⁵ is cycloalkyl. In some embodiments, R⁴ is —(CO)R² and R⁵ is aryl.

In some embodiments Formula (III), R⁴ is —(CO)R² and R⁵ is H.

In some embodiments of Formula (III), R⁴ is selected from the groupconsisting of ethyl sulfonyl, methyl sulfonyl and cyclopropyl sulfonyl.In some embodiments R⁴ is ethyl sulfonyl. In some embodiments R⁴ ismethyl sulfonyl. In some embodiments, R⁴ is selected from the groupconsisting of —(SO₂)-alkyl and —(CO)-aryl. In some embodiments, thealkyl or aryl are optionally substituted with one or more halogens.

In some embodiments of Formula (III), R⁵ is selected from the groupconsisting of phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl,3-trifluoromethylphenyl, 3,4-difluorophenyl, and 2,6-difluorophenyl. Insome embodiments, R⁵ is cyclopropyl. In some embodiments, R⁵ is selectedfrom the group consisting of pyridin-3-yl and 1-methylindazole-6-yl. Insome embodiments, R⁵ is selected from the group consisting of H,pyridin-2-yl, 3-chlorophenyl, and phenyl.

In some embodiments of Formula (III), R¹ is

X¹ is CH, X² is N; and X³ is CH; Y is CR² or N; R⁴ and R⁵ together withthe atom to which they are attached form a cycloalkyl or heterocyclyl;and variables R², R³, and n are as defined above for Formula (III).

In some embodiments of Formula (III), R¹ is

In some embodiments, R¹ is

In some embodiments, R^(a) is H, halo, C₁₋₃alkyl, or haloalkyl. In someembodiments, R^(a) is H. In some embodiments, R^(a) is C₁₋₃alkyl. Insome embodiments, R^(a) is haloalkyl. In some embodiments, halo is F. Insome embodiments, the C₁₋₃alkyl alkyl is methyl, ethyl or isopropyl. Insome embodiments, haloalkyl is CF₃, CHF₂, or CH₂F.

In some embodiments, the compounds of Formula (III) are selected fromthe group consisting of:

  and

.

Compounds of Formula (IV)

In some embodiments, the present disclosure provides a compound ofFormula (IV) or a pharmaceutically acceptable salt thereof:

whereinR¹ is selected from the group consisting of:

  and

;R^(a) is selected from the group consisting of H, halo, C₁₋₃ alkyl,cycloalkyl, haloalkyl, and alkoxy;R² and R³ are independently selected from the group consisting of H,halogen, alkoxy, haloalkyl, aryl, heteroaryl, alkyl, and cycloalkyl eachof which is optionally substituted, or R² and R³ together with the atomto which they are attached form a cycloalkyl or heterocyclyl;R⁴ and R⁵ are independently selected from the group consisting of H,(SO₂)R², —(SO₂)NR²R³, —(CO)R², —(CONR²R³), aryl, arylheteroaryl,heteroaryl, cycloalkyl, heterocyclyl, alkyl, haloalkyl, and alkoxy, eachof which is optionally substituted, or R⁴ and R⁵ together with the atomto which they are attached form a cycloalkyl or heterocyclyl;X¹ is selected from the group consisting of O, S, NH, or NR⁶, wherein R⁶is selected from the group consisting of C₁-C₆ alkyl, alkoxy, haloalkyl,cycloalkyl and heterocyclyl; andY is selected from the group consisting of CR², O, N, S, SO, and SO₂,wherein when Y is O, S, SO, or SO₂, R⁵ is not present and when R⁴ and R⁵together with the atom to which they are attached form a cycloalkyl orheterocyclyl, Y is CR² or N; andn is selected from 0, 1, or 2.

In some embodiments of Formula (IVa) and (IVb), n is 0. In someembodiments, n is 1. In some embodiments n is 2. In some embodiments nis 1 or 2.

In some embodiments Formula (IVa) and (IVb), X¹ is O. In someembodiments, X¹ is NH. In some embodiments, X¹ is NR⁶. In someembodiments, X¹ is NCH₃. In some embodiments X¹ is O or NCH₃.

In some embodiments of Formula (IVa) and (IVb), R² and R³ are H.

In some embodiments of Formula (IVa) and (IVb), Y is N.

In some embodiments of Formula (IVa) and (IVb), R⁴ is —(SO₂)R² and R⁵ isaryl. In some embodiments, R⁴ is —(SO₂)R² and R⁵ is heteroaryl. In someembodiments, R⁴ is —(SO₂)R² and R⁵ is cycloalkyl. In some embodiments,R⁴ is —(CO)R² and R⁵ is aryl. In some embodiments, R⁴ is —(CO)R² and R⁵is H.

In some embodiments of Formula (IVa) and (IVb), R⁴ is selected from thegroup consisting of ethyl sulfonyl, methyl sulfonyl and cyclopropylsulfonyl. In some embodiments, R^(a) is selected from the groupconsisting of —(SO₂)-alkyl, —(SO₂)-cycloalkyl, —(CO)-alkyl, —(CO)-aryland —(CO)-cycloalkyl. In some embodiments the alkyl, cycloalkyl and arylare optionally substituted with one or more halogen atoms.

In some embodiments of Formula (IVa) and (IVb), R⁵ is selected from thegroup consisting of phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl,3-trifluoromethylphenyl, 3,4-difluorophenyl, and 2,6-difluorophenyl. Insome embodiments, R⁵ is cyclopropyl. In some embodiments, R⁵ selectedfrom the group consisting of pyridin-3-yl and 1-methylindazole-6-yl. Insome embodiments, R⁵ is 3-chlorophenyl,

In some embodiments of Formula (IVa) and (IVb), R¹ is

In some embodiments of Formula (IVa) and (IVb), R^(a) is H, halo,C₁₋₃alkyl, or haloalkyl. In some embodiments, R^(a) is H. In someembodiments, R^(a) is C₁₋₃alkyl. In some embodiments, R^(a) ishaloalkyl. In some embodiments, halo is F. In some embodiments, theC₁₋₃alkyl alkyl is methyl, ethyl or isopropyl. In some embodiments,haloalkyl is CF₃, CHF₂, or CH₂F.

In some embodiments, the compound of Formula (IVa) or Formula (IVb) isselected from the group consisting of:

In some embodiments, the compound of the present disclosure is acompound of Table 3. In some embodiments, the compound of the presentdisclosure is a compound of Table 4.

In some embodiments, the compounds of the present disclosure encompassany isotopically-labeled (or “radio-labelled”) derivatives of a compounddescribed herein. Such a derivative is a derivative of a compound havinga formula described herein wherein one or more atoms are replaced by anatom having an atomic mass or mass number different from the atomic massor mass number typically found in nature. Examples of radionuclides thatmay be incorporated include ²H (also written as “D” for deuterium). Assuch, in one embodiment, a compound of Formula (I), Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), Formula (Id-1), Formula(Id-2), Formula (Id-3), Formula (Id-4), Formula (Ie), Formula (Ie-1),Formula (If), Formula (If-1), Formula (Ig), Formula (Ig-1), Formula(Ih), Formula (Ih-1), Formula (Ii), Formula (Ii-1), Formula (Ij),Formula (Ij-1), Formula (Ik), Formula (Ik-1), Formula (Ik-2), Formula(Ik-3), Formula (II), Formula (III), Formula (IVa), or Formula (IVb) isprovided where one or more hydrogen atoms are replaced by one or moredeuterium atoms.

Pharmaceutical Compositions

In various embodiments of the present disclosure, pharmaceuticalcompositions comprising one or more compounds disclosed herein, e.g., acompound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic),Formula (Id), Formula (Id-1), Formula (Id-2), Formula (Id-3), Formula(Id-4), Formula (Ie), Formula (Ie-1), Formula (If), Formula (If-1),Formula (Ig), Formula (Ig-1), Formula (Ih), Formula (Ih-1), Formula(Ii), Formula (Ii-1), Formula (Ij), Formula (Ij-1), Formula (Ik),Formula (Ik-1), Formula (Ik-2), Formula (Ik-3), Formula (II), Formula(III), Formula (IVa), or Formula (IVb) or a pharmaceutically acceptablesolvate, hydrate, tautomer, N-oxide, or salt thereof, and apharmaceutically acceptable excipient or adjuvant is provided. Thepharmaceutically acceptable excipients and adjuvants are added to thecomposition or formulation for a variety of purposes. In someembodiments, a pharmaceutical compositions comprising one or morecompounds disclosed herein, or a pharmaceutically acceptable solvate,hydrate, tautomer, N-oxide, or salt thereof, further comprise apharmaceutically acceptable carrier. In some embodiments, apharmaceutically acceptable carrier includes a pharmaceuticallyacceptable excipient, binder, and/or diluent. In some embodiments,suitable pharmaceutically acceptable excipients include, but are notlimited to, water, salt solutions, alcohol, polyethylene glycols,gelatin, lactose, amylase, magnesium stearate, talc, silicic acid,viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.

EXAMPLES

The invention is further illustrated by the following examples. Theexamples below are non-limiting are merely representative of variousaspects of the invention. Solid and dotted wedges within the structuresherein disclosed illustrate relative stereochemistry, with absolutestereochemistry depicted only when specifically, stated or delineated.

General Methods

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to a person skilled in the art and there may be several waysof purifying the same compound. In some cases, no purification may benecessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using e.g.prepacked silica gel cartridges, e.g. RediSep®R_(f) and eluents such asgradients of 0-100% EtOAc in hexanes or 0-100% of 10% MeOH in CH₂Cl₂

Purification methods as described herein may provide compounds of thepresent invention which possess a sufficiently basic or acidicfunctionality in the form of a salt, such as, in the case of a compoundof the present invention which is sufficiently basic, a trifluoroacetateor formate salt, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt. A salt of this type caneither be transformed into its free base or free acid form,respectively, by various methods known to a person skilled in the art orbe used as salts in subsequent biological assays. It is to be understoodthat the specific form of a compound of the present invention asisolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

All the starting materials and reagents are commercially available andwere used as is. ¹H Nuclear magnetic resonance (NMR) spectroscopy wascarried out using a Bruker Avance III instrument operating at 400 MHzusing the stated solvent at around room temperature unless otherwisestated. In all cases, NMR data were consistent with the proposedstructures. Characteristic chemical shifts (δ) are given inparts-per-million using conventional abbreviations for designation ofmajor peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd,doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.Preparative HPLC purification was performed by reverse phase HPLC usingAgilent Technologies 1200 Infinity Series or an equivalent HPLC systemsuch as Teledyne ISCO CombiFlash R_(f).

Chemical names were generated using the ChemDraw naming software(Version 17.0.0.206) by PerkinElmer Informatics, Inc. In some cases,generally accepted names of commercially available reagents were used inplace of names generated by the naming software.

Abbreviations

The following abbreviations are used in the examples, while otherabbreviations have their customary meaning in the art:

-   AIBN Azobisisobutyronitrile-   BOC: tert-butoxycarbonyl protecting group-   DCM: Dichloromethane-   DFAA: Difluoroacetic anhydride-   DIPEA: Diisopropylethylamine-   DMSO: Dimethylsulfoxide-   EDCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   EtOAc: Ethyl acetate-   h: hour(s)-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HCl: Hydrochloric acid-   HOBt: Hydroxybenzotriazole-   KO^(t)Bu: Potassium t-butoxide-   L: Liter-   LCMS: liquid chromatography-mass spectrometry-   M: Molar-   MeOH: Methanol-   min: Minute(s)-   μL: Microliter-   mL: Millliliter-   N: Normal-   NBS N-bromosuccinimide-   NMR: nuclear magnetic resonance spectroscopy-   ppm: parts per million-   rt: Room temperature-   tR: Retention time-   sat.: Saturated-   TEA: Triethylamine-   TFA Trifluoroacetic acid-   TFAA Trifluoroacetic anhydride-   THF: Tetrahydrofuran-   TSCl p-Toluenesulfonyl chloride

Analytical LC-MS Methods

Column: Eclipse Plus C18 4.6×3.5 μm; eluent A: 0.1% TEA in H₂O; eluentB: 0.1% TFA in CH₃CN; gradient: 20-100% over 4 minutes; flow: 1.5mL/min; injection volume 1-5 μL; temperature: 23° C.; UV scan: 220 and250 nm; signal settings—scan positive mode.

Analytical HPLC Methods

Column: Eclipse Plus C18 4.6×110 mm; eluent A: 0.1% TFA in H₂O; eluentB: 0.1% TFA in CH₃CN; gradient: 10-100% eluent B over 10 minutes; flow:1 mL/min; injection volume 1-5 μL; temperature: 23° C.; UV scan: 220,254 and 280 nm (method 1); 20-100% eluent B over 10 minutes; flow: 1mL/min; injection volume 1-5 μL; temperature: 23° C.; UV scan: 220, 254and 280 nm (method 2).

Preparative HPLC

Instrument: Agilent Technologies 1200 Infinity Series Column: Gemini 5μm NX-C18 110 Å, 250×21.2 mm; eluent A: 0.1% TFA in H₂O, eluent B: 0.1%TFA in CH₃CN; gradient: 10-100%; flow: 20 mL/min; injection volume 0.5-2mL; temperature: 23° C.; UV scan: 254 and 220 nm.

Synthesis of Compounds Example 1: General Scheme for the Synthesis ofCompounds of Formula (I) via Intermediate 4 and 6

Step 1: Preparation of tert-butyl2-(2-methylthiazole-5-carbonyl)hydrazine-1-carboxylate (2a).

(Tert-butoxy)carbohydrazide (21 g, 161 mmol) was taken up in DMF (300ml) and EDCI (31 g, 161 mmol) and benzotriazole (13 g, 94 mmol) wereadded. 2-Methyl-1,3-thiazole-5-carboxylic acid (1a, 20 g, 140 mmol) wasthen added and the resulting solution was cooled in an ice-bath.Diisopropylethylamine (53 ml, 307 mmol) was then added to the solutionslowly and the reaction was stirred for 36 h. TLC indicated that thereaction was complete. The solution was quenched by adding water andthen extracted with EtOAc (×2). The combined organic layers werefiltered through MgSO₄ and concentrated. The residue was purified onCombiflash (DCM/methanol) to give the product as a yellow foam. ¹H NMR(400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.01 (s, 1H), 8.23 (s, 1H) 2.69 (s,3H) 1.43 (s, 9H). LC-MS: tR (min) 3.15 (20-100% ACN with 0.1% TFA 6min), m/z [M+H]+ C₁₀H₁₆N₃O₃S requires: 258.3; found 258.0

Step 2: Preparation of2-(difluoromethyl)-5-(2-methylthiazol-5-yl)-1,3,4-oxadiazole (3a).

tert-Butyl 2-(2-methylthiazole-5-carbonyl)hydrazine-1-carboxylate (2.7g, 10.5 mmol) was taken up in DCM (100 ml) and cooled in an ice-bath.Trifluoroacetic acid (8.0 ml, 105 mmol) was added dropwise to thesolution and the reaction solution was stirred for 18 h at roomtemperature. TLC indicated that the reaction was complete. The solutionwas concentrated to give the hydrazide salt as a yellow oil. Theresulting oil was dissolved in DMF (100 mL) and triethylamine (11.7 mL,84 mmol) was added. Difluoroacetic anhydride (2.6 mL, 21 mmol) was thenadded and the solution was heated at 80° C. for 16 h. After cooling toroom temperature, the solution was diluted with EtOAc and washed withwater. The organic layer was filtered through MgSO₄ and concentrated.The resulting residue was purified on Combiflash (hexanes/EtOAcgradient) to afford the title compound (1.0 g, 44%) as an off-whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H) 6.90 (t, J=51.6 Hz, 1H)2.83 (s, 3H). LC-MS: tR (min) 3.65 (20-100% ACN with 0.1% TFA 6 min),m/z C₇H₆N₃F₂OS requires: 217.2; found 218.0. HPLC Rt 5.35 min; 97.2%(10-100% ACN with 0.1% TFA 10 min.)

Step 3: Preparation of2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole(4a)

2-(difluoromethyl)-5-(2-methylthiazol-5-yl)-1,3,4-oxadiazole (1.2 g, 5.5mmol) was taken up in 1,2-dichloroethane (200 ml) withN-bromosuccinimide (1.7 g, 9.9 mmol) and2-[(1E)-2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropanenitrile (91mg, 0.55 mmol) was added. The resulting solution was heated to refluxfor 5 h. The solution was cooled to room temperature and concentrated.The residue was purified on Combiflash (hexanes/EtOAc) gradient toafford the title product (1.0 g, 63%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.43 (s, 1H) 6.20 (t, J=51.6 Hz, 1H) 4.78 (s, 2H). LC-MS: tR(min) 4.44 (20-100% ACN with 0.1% TFA 6 min), m/z [M+H]⁺ C₇H₅BrF₂N₃OSrequires: 296.1; found 295.9, 297.9.

Example 2. Synthesis of Amide Compounds of Formula (I)—NucleophilicSubstitution

Preparation of4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)mnethyl)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one:

2,2-Dimethyl-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-one (40 mg, 0.22 mmol)was taken up in DMF (0.7 ml) in an ice-bath. Sodium hydride (10 mg, 60wt %, 0.22 mmol) was added and the solution was stirred for 20 min at 0°C. A solution of2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole(4a, 50 mg, 0.17 mmol) in DMF (0.5 ml) was then added dropwise at 0° C.The solution was stirred at room temperature for 4 h. TLC indicted thatthe reaction was complete (all the bromide was consumed). The reactionwas quenched by adding water and the separated aqueous phase wasextracted with EtOAc. The organic layer was collected, washed with brineand then filtered through MgSO₄. The filtrate was concentrated, and theresidue was purified on Combiflash (DCM/methanol gradient) to afford thetitle compound (42 mg, 63%) as a white powder.

Preparation ofN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholin-4-yl)-N-(pyridin-3-yl)propenamide(I-185)

Step : 3-morpholino-N-(3-pyridyl)propanamide

A mixture of 3-chloropyridine (359 mg, 3.16 mmol),3-morpholinopropanamide (500 mg, 3.16 mmol),tris(dibenzylideneacetone)dipalladium(0) (145 mg, 0.16 mmol),ditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane(38 mg, 0.08 mmol) and potassium phosphate (1.0 g, 4.74 mmol) intert-butanol (10 mL) was heated at 110° C. for 16 h under nitrogen andfiltered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography(silica gel, 100-200 mesh, 0-7% methanol in dichloromethane) to afford3-morpholino-N-(3-pyridyl)propanamide (675 mg, 84%) as a brown oil.

Step 2:N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholin-4-yl)-N-(pyridin-3-yl)propanamide

To a solution of 3-morpholino-N-(3-pyridyl)propanamide (286 mg, 1.22mmol) in tetrahydrofuran (5 mL) was added sodium hydride (60%, 41 mg,1.01 mmol). After stirring at 0° C. for 30 minutes,2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,300 mg, 1.01 mmol) was added. The mixture was stirred at 20° C. for 1 hand filtered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by RP-HPLC (0 to 20% acetonitrile inwater and 0.225% formic acid) to affordN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholin-4-yl)-N-(pyridin-3-yl)propanamide(3.4 mg, 3.7%) as a colorless oil.

Preparation of1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H,4H,5H-pyrido[4,3-b]azepin-2-one(I-200)

Step 1: tert-butyl (E)-4-(4-amino-3-pyridyl)but-3-enoate

A mixture of 3-bromopyridin-4-amine (1.0 g, 5.78 mmol), tert-butylbut-3-enoate (3.3 g, 23.12 mmol), triethylamine (2.3 g, 23.12 mmol),palladium(II) acetate (130 mg, 0.58 mmol) and tris-o-tolylphosphane (352mg, 1.16 mmol) in N,N-dimethylformamide (50 mL) was heated at 120° C.for 16 h and filtered. The filtrate was concentrated to dryness underreduced pressure. The residue was purified by flash columnchromatography (silica gel, 100-200 mesh, 0-10% methanol indichloromethane) to afford tert-butyl(E)-4-(4-amino-3-pyridyl)but-3-enoate (431 mg, 30%) as a brown oil.

Step 2: tert-butyl 4-(4-amino-3-pyridyl)butanoate

A mixture of tert-butyl (E)-4-(4-amino-3-pyridyl)but-3-enoate (331 mg,1.41 mmol) and palladium (10% on carbon, 33 mg, 0.03 mmol) in methanol(30 mL) was hydrogenated (15 psi) at 20° C. for 16 h and filtered. Thefiltrate was concentrated to dryness under reduced pressure. The residuewas purified by flash column chromatography (silica gel, 100-200 mesh,0-7% methanol in dichloromethane) to afford tert-butyl4-(4-amino-3-pyridyl)butanoate (354 mg, 78%) as a yellow oil.

Step 3: 1,3,4,5-tetrahydropyrido[4,3-b]azepin-2-one

To a solution of tert-butyl 4-(4-amino-3-pyridyl)butanoate (284 mg, 1.20mmol) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (674mg, 6.01 mmol). After stirring at 20° C. for 1 h, the reaction mixturewas diluted with ethyl acetate (20 mL), washed with brine (20 mL), driedover sodium sulphate and concentrated to dryness under reduced pressureto afford crude 1,3,4,5-tetrahydropyrido[4,3-b]azepin-2-one (77 mg,crude) as a yellow solid,

Step 4:1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H,4H,5H-pyrido[4,3-b]azepin-2-one

To a solution of 1,3,4,5-tetrahydropyrido[4,3-b]azepin-2-one (33 mg,0.20 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride(60%, 7 mg, 0.19 mmol). After stirring at 0° C. for 0.5 hour,2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,50 mg, 0.17 mmol) was added. The mixture was stirred at 20° C. foranother 0.5 h and filtered. The filtrate was concentrated to drynessunder reduced pressure. The residue was purified by RP-HPLC (0 to 40%acetonitrile in water and 0.225% formic acid) to afford1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H,4H,5H-pyrido[4,3-b]azepin-2-one(13.3 mg, 20%) as a yellow oil.

Preparation of1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3,3-dimethyl-4,5-dihydropyrido[3,4-b]azepin-2-one(I-253)

Step 1: benzyl 2,2-dimethylbut-3-enoate

To a solution of 2,2-dimethylbut-3-enoic acid (1.0 g, 8.76 mmol) inN,N-dimethylformamide (20 mL) was added potassium carbonate (2.4 g,17.52 mmol). The mixture was stirred at 20° C. for 5 minutes, thenbenzyl bromide (1.7 g, 9.64 mmol) was added. After stirring at 20° C.for 16 hours, the reaction mixture was filtered. The filtrate wasdiluted with ethyl acetate (100 mL) and washed with brine (3×100 mL).The separated organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate inpetroleum ether) to afford benzyl 2,2-dimethylbut-3-enoate (1.20 g, 67%)as colorless oil.

Step 2: benzyl (E)-4-(3-amino-4-pyridyl)-2,2-dimethyl-but-3-enoate

To a solution of benzyl 2,2-dimethylbut-3-enoate (1.1 g, 5.39 mmol) and4-bromopyridin-3-amine (466 mg, 2.69 mmol) in 1,4-dioxane (15 mL) wasadded N-cyclohexyl-N-methyl-cyclohexanamine (1.47 g, 7.54 mmol),Pd₂(dba)₃ (123 mg, 0.13 mmol) and P(t-Bu)₃ (138 mg, 0.27 mmol). Afterstirring at 110° C. for 16 hours under nitrogen atmosphere, the reactionmixture was filtered. The filtrate was concentrated under reducedpressure. The residue was purified column chromatography (silica gel,100-200 mesh, 0-70% ethyl acetate in petroleum ether) to afford benzyl(E)-4-(3-amino-4-pyridyl)-2,2-dimethyl-but-3-enoate (712 mg, 81%) as alight yellow oil.

Step 3: 4-(3-amino-4-pyridyl)-2,2-dimethyl-butanoic acid

To a solution of benzyl(E)-4-(3-amino-4-pyridyl)-2,2-dimethyl-but-3-enoate (612 mg, 2.07 mmol)in methanol (30 mL) was added palladium (220 mg, 0.21 mmol, 10% oncarbon). After stirring at 20° C. under hydrogen (15 psi) for 16 hours,the mixture was filtered. The filtrate was concentrated under reducedpressure. The residue was purified column chromatography (silica gel,100-200 mesh, 0-10% methanol in dichloromethane) to afford4-(3-amino-4-pyridyl)-2,2-dimethyl-butanoic acid (250 mg, 58%) as alight yellow solid.

Step 4: 3,3-dimethyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2-one

To a solution of 4-(3-amino-4-pyridyl)-2,2-dimethyl-butanoic acid (250mg, 1.20 mmol) in N,N-dimethylformamide (3 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (479 mg, 1.26 mmol) andN-ethyl-N-isopropylpropan-2-amine (310 mg, 2.40 mmol) at 0° C. Afterstirring at 20° C. for 2 hours, the reaction mixture was diluted withethyl acetate (50 mL) and washed with brine (3×50 mL). The separatedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-10% methanol indichloromethane) to afford3,3-dimethyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2-one (340 mg, crude) asa light yellow solid.

Step 5:1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3,3-dimethyl-4,5-dihydropyrido[3,4-b]azepin-2-one

To a solution of 3,3-dimethyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2-one(50 mg, 0.26 mmol) in N,N-dimethylformamide (1 mL) was added sodiumhydride (60%, 8 mg, 0.20 mmol). After stirring at 0° C. for 30 mins, themixture was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (60mg, 0.20 mmol) and stirred for another 0.5 hour. The reaction mixturewas filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by RP-HPLC (25 to 55% acetonitrile in water and0.225% formic acid) to afford1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3,3-dimethyl-4,5-dihydropyrido[3,4-b]azepin-2-one(28 mg, 32%) as a light yellow solid.

Preparation of1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one(I-252);(S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one(I-246);(R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one(I-245)

Step 1: benzyl 2-methylbut-3-enoate

To a solution of 2-methylbut-3-enoic acid (1.0 g, 9.99 mmol) indichloromethane (1 mL) was added benzyl alcohol (1.1 g, 9.99 mmol),N,N-dicyclohexylcarbodiimide (2.1 g, 9.99 mmol) anddimethylaminopyridine (122 mg, 1.00 mmol). After stirring at 20° C. for16 hours, the reaction mixture was filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate inpetroleum ether) to afford benzyl 2-methylbut-3-enoate (1.8 g, 95%) ascolorless oil.

Step 2: benzyl 4-(3-aminopyridin-4-yl)-2-methylbut-3-enoate

To a solution of 4-bromopyridin-3-amine (1.1 g, 6.36 mmol) in1,4-dioxane (20 mL) was added benzyl 2-methylbut-3-enoate (1.7 g, 8.90mmol), Pd₂(dba)₃ (291 mg, 0.32 mmol), tritert-butylphosphane palladium(325 mg, 0.64 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (3.7 g,19.07 mmol). After stirring at 110° C. under nitrogen atmosphere for 16hours, the reaction mixture was filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by RP-HPLC (10 to 40%acetonitrile in water and 0.225% formic acid) to afford benzyl4-(3-amino-4-pyridyl)-2-methyl-but-3-enoate (900 mg, 47%) as yellow oil.

Step 3: 4-(3-aminopyridin-4-yl)-2-methylbutanoic acid

To a solution of benzyl 4-(3-amino-4-pyridyl)-2-methyl-but-3-enoate (800mg, 2.83 mmol) in methanol (10 mL) was added palladium (302 mg, 0.28mmol, 10% on carbon). After stirring at 20° C. under hydrogen atmosphere(15 psi) for 16 hours, the reaction mixture was filtered. The filtratewas concentrated to dryness under reduced pressure to afford crude4-(3-amino-4-pyridyl)-2-methyl-butanoic acid (500 mg, 91%) as yellowoil.

Step 4: 3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one

To a mixture of 4-(3-amino-4-pyridyl)-2-methyl-butanoic acid (500 mg,2.57 mmol) in N,N-dimethylformamide (0.5 mL) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (979 mg, 2.57 mmol) andN-ethyl-N-isopropylpropan-2-amine (998 mg, 7.72 mmol). After stirring at20° C. for 16 hours, the reaction mixture was diluted with ethyl acetate(60 mL) and washed with brine (3×30 mL). The separated organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,100-200 mesh, 0-10% methanol in dichloromethane) to afford3-methyl-1,3,4,5-tetrahydropyrido[3,4-b]azepin-2-one (800 mg, crude) asyellow oil.

Step 5:1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one;(S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-oneand(R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-4,5-dihydro-1H-pyrido[3,4-b]azepin-2(3H)-one

To a solution of 3-methyl-1,3,4,5-tetrahydropyrido[3,4-b]azepin-2-one(45 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was added sodiumhydride (60%, 7 mg, 0.17 mmol, 60%) at 0° C. After stirring at 0° C. for30 min, the reaction was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50mg, 0.17 mmol). After stirring at 20° C. for another 30 minutes, thereaction mixture was filtered. The filtrate was concentrated underreduced pressure, the residue was purified by RP-HPLC (15 to 45%acetonitrile in water and 0.225% formic acid) to afford1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3-methyl-4,5-dihydro-3H-pyrido[3,4-b]azepin-2-one(3.5 mg, 5%) as a white solid.

Another batch of the racemic material (100 mg, 0.26 mmol) was furtherseparated by SFC to afford arbitrarily assigned:

(3S)-1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3-methyl-4,5-dihydro-3H-pyrido[3,4-b]azepin-2-one(Peak 1, retention time=3.001 min) (49.5 mg, 49%) as a light yellowsolid.

LCMS (0 to 60%, 0.018% TFA in acetonitrile 0.037% TFA in water over 4min)

Retention time 1.251 min, ESI+found [M+H]⁺=392.3.

(3R)-1-[[5-[5-(difluoromethy)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-3-methyl-4,5-dihydro-3H-pyrido[3,4-b]azepin-2-one(Peak 2, retention time=3.310 min) (49.8 mg, 49%) as a light yellowsolid.

LCMS (0 to 60%, 0.018% TFA in acetonitrile+0.037% TFA in water over 4min)

Retention time 1.250 min, ESI+found [M+H]⁺=392.3.

SFC condition: Column: Chiral ND-3 100×4.6 mm I. D., 3 um, Mobile phase:A: CO₂ B: iso-propanol (0.05% DEA), Gradient: from 5% to 40% of B in 4.5min and hold 40% for 2.5 min, then 5% of B for 1 min, Flow rate: 2.8mL/min, Column temperature: 40° C.

Preparation of1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one(I-255);(R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one(I-250); and(S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one(I-251)

Step 1: methyl 3-(3-aminopyridin-4-yl)-2-methylacrylate

To a solution of 4-bromopyridin-3-amine (2.0 g, 11.56 mmol) inN,N-dimethylacetamide (2 mL) was added methyl 2-methylprop-2-enoate (2.3g, 23.12 mmol), tetrabutyl ammonium chloride (321 mg, 1.16 mmol),N-cyclohexyl-N-methyl-cyclohexanamine (3.6 g, 18.50 mmol) andditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (753 mg, 1.16mmol). Ater stirring at 80° C. for 16 hours, the reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure. Theresidue was diluted with ethyl acetate (100 mL) and washed with brine(3×100 mL). The separated organic extract was dried over anhydroussodium sulphate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0-100%ethyl acetate in petroleum ether) to afford methyl3-(3-aminopyridin-4-yl)-2-methylacrylate (1.8 g, 81%) as colorless oil.

Step 2: 3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one

To a solution of methyl methyl 3-(3-aminopyridin-4-yl)-2-methylacrylate(1.5 g, 7.80 mmol) in methanol (2 mL) was added palladium (1.6 g, 1.56mmol, 10% on carbon). After stirring at 50° C. under hydrogen (45 psi)for 16 hours, the reaction mixture was filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified bypreparative TLC (dichloromethane:methanol=10:1) to afford3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (300 mg, 23%) as a whitesolid.

Step 3:1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one;(R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-oneand(S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one

To a solution of 3-methyl-3,4-dihydro-1H-1,7-naphthyridin-2-one (150 mg,0.92 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride(60%, 33 mg, 0.84 mmol) at 0° C. After stirring at 0° C. for 0.5 hour,the reaction was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,248 mg, 0.84 mmol). After stirring at 20° C. for another 0.5 hour, thereaction mixture was filtered. The filtrate was concentrated underreduced pressure. The residue was purified by RP-HPLC (8 to 48%acetonitrile in water and 0.225% formic acid) to afford 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one(120 mg, 36%) as a white solid.

The above racemic material (100 mg, 0.26 mmol) was further separated bySFC to afford arbitrarily assigned:

(R)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one(Peak 1, retention time=1.984 min) (24.7 mg, 24%) as colorless oil.

(S)-1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-methyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one(Peak 2, retention time=2.744 min) (31.4 mg, 29%) as colorless oil.

SFC condition: Column: Chiral NS-3 100×4.6 mm I.D., 3 um Mobile phase:A: CO₂ B: ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 4 minand hold 40% for 2.5 min, then 5% of B for 1.5 min, Flow rate: 2.8mL/min, Column temperature: 40° C.

Preparation of1′-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridine]-2′-one(I-247)

Step 1: ethyl 2-(3-bromo-4-pyridyl)acetate

To a mixture of 3-bromo-4-methyl-pyridine (5.0 g, 29.07 mmol) anddiethyl carbonate (4.0 g, 34.30 mmol) in tetrahydrofuran (50 mL) wasadded lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 46.0mL, 46.0 mmol) at 0° C. After stirring at 0° C. for 3 hours undernitrogen atmosphere, the mixture was poured into saturated aqueousammonium chloride solution (100 mL) carefully and extracted with ethylacetate (3×100 mL). The combined organic phases were dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-6% ethyl acetate in petroleum ether) to afford ethyl2-(3-bromo-4-pyridyl)acetate (5.68 g, 75%) as colorless oil.

Step 2: ethyl 1-(3-bromo-4-pyridyl)cyclopropanecarboxylate

To a solution of ethyl 2-(3-bromo-4-pyridyl) acetate (500 mg, 2.05 mmol)in N,N-dimethylformamide (35 mL) was added sodium hydride (60%, 180 mg,4.51 mmol) at 0° C. After stirring at 0° C. for 15 minutes, the reactionwas added 1,2-dibromoethane (385 mg, 2.05 mmol). The mixture was stirredfor 30 minutes at 30° C. and then added another batch of sodium hydride(60%, 41 mg, 1.02 mmol). Upon completion by monitoring by TLC, thereaction mixture was poured into water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic extracts were dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0-3% ethylacetate in petroleum ether) to afford ethyl1-(3-bromo-4-pyridyl)cyclopropanecarboxylate (390 mg, 47%) as acolorless oil.

Step 3: ethyl1-[3-(benzhydrylideneamino)-4-pyridyl]cyclopropanecarboxylate

A mixture of ethyl 1-(3-bromo-4-pyridyl)cyclopropanecarboxylate (1.1 g,4.00 mmol), diphenylmethanimine (797 mg, 4.40 mmol), Pd₂(dba)₃ (183 mg,0.2 mmol), BINAP (249 mg, 0.4 mmol) and sodium tert-butoxide (576 mg,6.00 mmol) in toluene (10 mL) was stirring at 80° C. for 16 hours undernitrogen atmosphere. The reaction mixture was filtered, and the filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate inpetroleum ether) to afford ethyl1-[3-(benzhydrylideneamino)-4-pyridyl]cyclopropanecarboxylate (836 mg,50%) as a yellow solid.

Step 4: ethyl 1-(3-amino-4-pyridyl)cyclopropanecarboxylate

To a solution of ethyl1-[3-(benzhydrylideneamino)-4-pyridyl]cyclopropanecarboxylate (736 mg,1.99 mmo) in tetrahydrofuran (7 mL) was added hydrochloric acid (1.0 Min water, 22.0 mL, 22.00 mmol). After stirring at 20° C. for 1 hour, themixture was diluted with water (30 mL) and washed with ethyl acetate(2×20 mL). The water phase was adjusted to pH 8 with sodium carbonateand extracted with dichloromethane (3×20 mL). The combined organicextracts were dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford crude ethyl1-(3-amino-4-pyridyl)cyclopropanecarboxylate (300 mg) as yellow oil.

Step 5: spiro[1H-pyrrolo[2,3-c]pyridine-3,1′-cyclopropane]-2-one

To a solution of ethyl 1-(3-amino-4-pyridyl)cyclopropanecarboxylate (250mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added potassiumtert-butoxide (272 mg, 2.42 mmol). The mixture was stirring at 20° C.for 1 hour. The mixture was filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-10% methanol indichloromethane) to affordspiro[1H-pyrrolo[2,3-c]pyridine-3,1′-cyclopropane]-2-one (185 mg, 64%)as a colorless oil.

Step 6:1′-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridine]-2′-one

To a solution ofspiro[1H-pyrrolo[2,3-c]pyridine-3,1′-cyclopropane]-2-one (19 mg, 0.13mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 4mg, 0.11 mmol) at 0° C. After stirring at 0° C. for 30 minutes, thereaction was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,30 mg, 0.11 mmol). After stirring at 20° C. for 1 hour, the mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by RP-HPLC (0 to 30% acetonitrile in water and0.225% formic acid) to afford 1′-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]spiro[cyclopropane-1,3′-pyrrolo[2,3-c]pyridine]-2′-one(10.8 mg, 17%) as a yellow solid.

Preparation of1-({5-[5-(difluoromethyl)-1,34-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-2-one(I-176)

Step 1: 2-chloro-N-(3-hydroxy-4-pyridyl)acetamide

A mixture of 4-aminopyridin-3-ol (200 mg, 1.82 mmol) and 2-chloroacetylchloride (2 mL) was stirred at 80° C. for 2 h and concentrated underreduced pressure. The residue was diluted with water (10 mL) andneutralized by addition of saturated aqueous sodium bicarbonate. Thesolid precipitate was collected by filtration and dried under reducedpressure to afford 2-chloro-N-(3-hydroxy-4-pyridyl)acetamide (324 mg,93%) as a white solid.

Step 2: 1H-pyrido[3,4-b][1,4]oxazin-2-one

To a solution of 2-chloro-N-(3-hydroxy-4-pyridyl)acetamide (324 mg, 1.74mmol) in water (8 mL) was added potassium carbonate (324 mg, 2.34 mmol).The mixture was stirred at 20° C. for 16 h and concentrated to drynessunder reduced pressure. The residue was washed with methanol (2 mL) andhot ethyl acetate (2 mL). The solid was collected by filtration anddried under reduced pressure to afford crude1H-pyrido[3,4-b][1,4]oxazin-2-one (370 mg) as a white solid.

Step 3:1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-2-one

To a solution of 1H-pyrido[3,4-b][1,4]oxazin-2-one (101 mg, 0.68 mmol)in tetrahydrofuran (2 mL) was added sodium hydride (60%, 15 mg, 0.37mmol, 60% purity) at 0° C. under nitrogen atmosphere. After stirring at0° C. for 0.5 h, the mixture was added a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,100 mg, 0.34 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at25° C. for 16 h and quenched by addition of saturated aqueous ammoniumchloride (6 mL). The resulting solution was extracted with ethyl acetate(3×6 mL). The combined organic layers were dried over anhydrous sodiumsulphate and concentrated under reduced pressure. The residue waspurified by RP-HPLC (0 to 30% acetonitrile in water and 0.225% formicacid) to afford1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H-pyrido[3,4-b][1,4]oxazin-2-one(4.6 mg, 4%) as a light yellow oil.

The methods described in Example 2 were also used to prepare thefollowing compounds: I-171, I-172, I-173, I-186, I-195, I-198, I-199,I-200, I-209, I-210, I-248, I-249, I-254, I-256, I-269, and I-270.

Example 3. Synthesis of Amide Compounds of Formula (I)—Via Pd Coupling

Preparation of(R)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one(Compound I-43) and(S)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one(Compound I-44).

A solution of methyl 2-bronco-1,3-thiazole-5-carboxylate (2 g, 9.01mmol) in THF/water/methanol 3:2:1 (24 mL:16 mL:8 mL) was treated withLiOH (2 eq, 431 mg, 18 mmol). After 5 min at rt LCMS showed completeconversion. The mixture was neutralized to pH 7 and concentrated. Theresidual aqueous layer was acidified with 6 N HCl to pH 1. Theprecipitate was filtered, washed with water and little amount of hexane(the desired product dissolved in hexane partially). The solid was driedin high vacuum for 2 hours, transferred to a pear-shaped flask, rinsedwith toluene 3× (to remove moisture azeotropically) and dried again inhigh vacuum to yield 1.80 g (96%) of 2-bromothiazole-5-carboxylic acidas white solid.

To a cooled (0° C.) solution of amine (1.25 g, 6 mmol),({[3-(dimethylamino)propyl]imino}-methylidene)(ethyl)amine hydrochloride(1.1 eq, 1.27 g, 6.61 mmol), (tert-butoxy)carbohydrazide (1.3 eq, 1.03g, 7.81 mmol) and 1H-1,2,3-benzotriazol-1-ol (1.3 eq, 1.06 g, 7.81 mmol)in DMF (20 mL) was added dropwise DIPEA (4 eq, 3.11 g, 4.19 mmol, 24mmol). After 90 min LCMS showed complete conversion. The mixture waspoured into water and brine (1:1, 300 mL) and extracted with EtOAc (3×).The combined organics were washed with brine (3×), and dried (Na²SO4)and concentrated to give yellow oil 3.5 g. The crude material waspurified by column chromatography (80g SiO₂, 0-50% EA in hexane). Yield:1.39 g (72%) of2-bromo-N′-[(tert-butoxy)carbonyl]-1,3-thiazole-5-carbohydrazide aswhite solid.

To a cooled (0° C.) solution of2-bromo-N′-[(tert-butoxy)carbonyl]-1,3-thiazole-5-carbohydrazide (819mg, 2.54 mmol) in anhydrous DCM (7 mL) was added 4 M HCl in dioxane (15eq, 38.1 mmol, 9.53 mL) dropwise. The mixture was stirred at rt for 16hours. LCMS showed complete conversion. The mixture was treated with a1:3 mixture of MTBE:hexane (50 mL). The precipitate was filtered off,washed with hexane and dried in high vacuum. Yield: 529.7 mg (80%) of2-bromothiazole-5-carbohydrazide hydrochloride as off-white solid.

A suspension of 2-bromo-1,3-thiazole-5-carbohydrazide HCl (250 mg, 0.968mmol) in anhydrous THF (5 mL) was treated with triethylamine (6 eq, 588mg, 0.81 mL, 5.81 mmol) followed by difluoroacetic anhydride (2 eq, 344mg, 0.215 mL, 1.94 mmol). The mixture was stirred at 70° C. for 21hours. LCMS indicated total consumption of the starting material butshowed neither the desired mass, nor the distinctive bromide mass.However, a small sample was reacted with phenethylamine and the reactiongave the desired Sn—Ar product. This confirmed that the bromide wasintact. The mixture was quenched with water (0.3 mL) and concentrated.The residue was rinsed with dichloromethane and evaporated. The processwas repeated 4 times, 1.28 g residue was obtained and purified by columnchromatography (40 g SiO2, 0-10% MeOH in dichloromethane). Yield: 238.3mg (82%) of 2-bromo-N′-(2,2-difluoroacetyl)thiazole-5-carbohydrazide asyellow solid.

A mixture of2-bromo-N′-(2,2-difluoroacetyl)-1,3-thiazole-5-carbohydrazide (154 mg,0.513 mmol) and Burgess reagent (5 eq, 619 mg, 2.57 mmol) in anhydrousTHF (5 mL) was heated in microwave at 150° C. for 90 min. LCMS showedcomplete conversion. The desired product didn't ionize well and[M+H]⁺=282/284 was not observed (however, in the previous step it wasproven that the bromide was intact). THF was removed in rotaryevaporator. The residue was partitioned in water and ethyl acetate. Thelayers were separated and the aqueous layer was extracted with ethylacetate (2×). The combined organics were washed with brine and dried(Na₂SO₄) and concentrated to give 146 mg crude material which waspurified by column chromatography (12 g SiO₂, 0-15% EA in hexane).Yield: 59.9 mg (41%) of2-(2-bromothiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole as whitesolid.

A mixture of2-(2-bromo-1,3-thiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (33.4mg, 0.118 mmol), (4R)-4-phenyl-1,3-oxazolidin-2-one (1.3 eq, 25 mg,0.149 mmol) and cesium carbonate (1.5 eq, 34.3 mg, 0.177 mmol) indioxane (2 mL) was flushed with nitrogen for 5 min. Xantphos (0.09 eq,6.14 mg, 0.01062 mmol) and Tetrakis(triphenylphosphine)-palladium (0.1eq, 13.6 mg, 0.0118 mmol) were added. The mixture was flushed withnitrogen for 10 min, sealed and heated in microwave at 125° C. for 2hours. LCMS showed complete conversion. The mixture was poured intowater and extracted with ethyl acetate (3×). The combined organics werewashed with water (3×), brine, dried (Na₂SO₄) and concentrated to give101 mg yellow solid. The crude material was purified by columnchromatography (4 g SiO₂, 0-50% EA in hexane). Yield: 15.6 mg (54%) of(R)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one(I-43) as yellow solid.

A mixture of2-(2-bromo-1,3-thiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (22.2mg, 0.079 mmol), (4S)-4-phenyl-1,3-oxazolidin-2-one (1.3 eq, 15.4 mg,0.0944 mmol) and cesium carbonate (1.5 eq, 22.9 mg, 0.118 mmol) indioxane (2 mL) was flushed with nitrogen for 5 min. Xantphos (0.09 eq,4.10 mg, 0.0071 mmol) and Tetrakis(triphenylphosphine)-palladium (0.1eq, 9.10 mg, 0.0079 mmol) were added. The mixture was flushed withnitrogen for 10 min, sealed and heated in microwave at 125° C. for 2hours. LCMS showed complete conversion. The mixture was poured intowater and extracted with ethyl acetate (3×). The combined organics werewashed with water (3×), brine, dried (Na₂SO₄) and concentrated to give60 mg yellow solid. The crude material was purified by columnchromatography (4 g SiO₂, 0-50% EA in hexane). Yield: 14.6 mg (51%) of(S)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one(I-44) as yellow solid.

The methods described in Example 3 were also used to prepare compoundI-101.

Example 4. Synthesis of Sulfonamide Compounds of Formula (I)

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)ethanesulfonamide(Compound I-6).

Step 1: Preparation of N-(pyridin-3-yl)ethanesulfonamide.

3-Aminopyridine (370 mg, 3.9 mmol) was taken up in DCM (15 mL) andcooled in an ice-bath. Pyridine (0.35 ml, 4.3 mmol) and ethanesulfonylchloride (0.4 ml, 0.43 mmol) were added and the resulting solutionstirred at room temperature for 16 h. The reaction was quenched byadding saturated brine and then extracted with DCM. The separatedorganic layer was filtered through MgSO₄ and then concentrated. Theresidue was purified on Combiflash (hexanes/EtOAc gradient) to affordthe title compound (120 mg, 17%) as a white powder.

Step 2: Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)ethanesulfonamide.

N-(Pyridin-3-yl)ethane-1-sulfonamide (31 mg, 0.17 mmol) was taken up inDMF (0.4 ml) in an ice bath. Sodium hydride (7 mg, 60% wt., 0.17 mmol)was then added and the solution stirred for 30 min in the ice-bath. Asolution of2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole(4a, 31 mg, 0.17 mmol) in DMF (0.5 ml) was then added and the reactionwas stirred at room temperature 16 h. TLC indicated that the reactionwas complete. The reaction was quenched by adding saturated NH₄Clsolution and then extracted with EtOAc. The organic layer was filteredthrough MgSO₄ and concentrated. The residue was purified on Combiflash(DCM/methanol gradient) to afford the title compound.

Preparation ofN-[5-(difluoromethoxy)-3-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide(Compound I-96).

Step 1: 3-(difluoromethoxy)-5-nitropyridine

To a solution of 5-nitropyridin-3-ol (500 mg, 3.57 mmol) inN,N-dimethylformamide (5 mL) was added potassium carbonate (1.48 g,10.71 mmol). The mixture was stirred at 20° C. for 30 minutes and then2-chloro-2,2-difluoro-acetate (1.4 g, 8.92 mmol) was added. The reactionmixture was stirred at 100° C. for 4 hours and filtered. The filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 100-200 mesh, 10-30% ethyl acetate inpetroleum ether) to afford 3-(difluoromethoxy)-5-nitro-pyridine (200 mg,29%) as yellow oil.

Step 2: 5-(difluoromethoxy)pyridin-3-amine

To a solution of 3-(difluoromethoxy)-5-nitro-pyridine (150 mg, 0.80mmol) in ethanol (2 mL) was added palladium (10% on carbon, 84 mg). Thereaction mixture was stirred under hydrogen atmosphere at 15 psi for 2hours and filtered. The filtrate was concentrated under reduced pressureto afford 5-(difluoromethoxy)pyridin-3-amine (150 mg, crude) as a yellowsolid.

Step 3: N-(5-(difluoromethoxy)pyridin-3-yl)ethnesulfonamide

To a solution of 5-(difluoromethoxy)pyridin-3-amine (130 mg, 0.8 mmol)in pyridine (2 mL) was added ethanesulfonyl chloride (125 mg, 0.97mmol). The reaction mixture was stirred at 20° C. for 16 hours andconcentrated under reduced pressure. The residue was purified by RP-TLC(dichloromethane:methanol=10:1) to affordN-[5-(difluoromethoxy)-3-pyridyl]ethanesulfonamide (200 mg, 98%) as awhite solid.

Step 4:N-[5-(difluoromethoxy)-3-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide(Compound II-96)

Prepared from2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazoleaccording to method described for I-6. The crude product was purified byRP-HPLC (50-80% acetonittile in water and 0.225% formic acid) to affordN-[5-(difluoromethoxy)-3-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide(19.7 mg, 30%) as a white solid.

Preparation ofN-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide(I-147)

Prepared from 5-(difluoromethoxy)pyridin-3-amine and methanesulfonylchloride according to method described for I-6. The crude product waspurified by RP-HPLC (35 to 65% acetonitrile in water and 0.225% formicacid) to affordN-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide(12 mg, 16%) as a light yellow solid.

Preparation ofN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2-difluoropropoxy)pyridin-3-yl]methanesulfonamide(I-224)

Step 1: 1-((5-bromopyridin-3-yl)oxy)propan-2-one

To a mixture of 5-bromopyridin-3-ol (2.0 g, 11.49 mmol) and1-chloropropan-2-one (1.3 g, 13.79 mmol) in N,N-dimethylformamide (20mL) was added potassium carbonate (1.8 g, 12.64 mmol). After stirring at20° C. for 16 h, the reaction mixture was diluted with ethyl acetate(100 mL), washed with brine (3×50 mL), dried and concentrated underreduced pressure. The residue was purified by flash columnchromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate inpetroleum ether) to afford 1-[(5-bromo-3-pyridyl)oxy]propan-2-one (2.6g, 93%) as a brown solid.

Step 2: 3-bromo-5-(2,2-difluoropropoxy)pyridine

To a solution of 1-[(5-bromo-3-pyridyl)oxy]propan-2-one (2.4 g, 10.43mmol) indichloromehtane (20 mL) was added diethylaminosulfur trifluoride(3.4 g, 20.86 mmol) at 0° C. The mixture was then stirred at 20° C. for2 h and poured to ice water (100 mL) carefully. The solution wasextracted with ethyl acetate (3×50 mL). The combined organic extractswere dried and concentrated under reduced pressure. The residue waspurified by flash column chromatography (silica gel, 100-200 mesh, 0-13%ethyl acetate in petroleum ether) to afford3-bromo-5-(2,2-difluoropropoxy)pyridine (1.85 g, 70%) as a yellow oil.

Step 3: 5-(2,2-difluoropropoxy)-N-(diphenylmethylene)pyridin-3-amine

To a solution of 3-bromo-5-(2,2-difluoropropoxy)pyridine (1.9 g, 7.34mmol) and diphenylmethanimine (1.5 g, 8.07 mmol) in toluene (20 mL) wasadded sodium tert-butoxide (1.1 g),(R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthalene (457 mg, 0.73 mmol)and tris(dibenzylideneacetone)dipalladium(0) (336 mg, 0.37 mmol). Themixture was heated at 80° C. under nitrogen atmosphere for 16 h andfiltered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography(silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) toafford N-[5-(2,2-difluoropropoxy)-3-pyridyl]-1,1-diphenyl-methanimine(2.64 g, 77%) as a yellow oil.

Step 3: 5-(2,2-difluoropropoxy)pyridin-3-amine

To a solution ofN-[5-(2,2-difluoropropoxy)-3-pyridyl]-1,1-diphenyl-methanimine (2.3 g,6.64 mmol) in tetrahydrofuran (2.3 mL) was added hydrochloric acid (2 M,6.0 mL, 12.0 mmol). The mixture was stirred at 20° C. for 2 h anddiluted with water (50 mL). The resulting solution was washed with ethylacetate (3×50 mL). The separated aqueous layer was adjusted to pH=8 byaddition of aqueous sodium hydroxide (1 M) and extracted withdichloromethane (3×20 mL). The combined organic extracts were dried andconcentrated under reduced pressure to afford crude5-(2,2-difluoropropoxy)pyridin-3-amine (1.32 g, crude) as a yellowsolid.

Step 4: N-[5-(2,2-difluoropropoxy)-3-pyridyl]methanesulfonamide

To a solution of 5-(2,2-difloropropoxy)pyridin-3-amine (100 mg, 0.53mmol) in pyridine (1 L) was added methanesulfonyl chloride (73 mg, 0.64mmol). The mixture was stirred at 20° C. for 16 and filtered. Thefiltrate was concentrated to dryness under reduced pressure. The residuewas purified by preparative TLC (dichloromethane:methanol=10:1) toafford N-[5-(2,2-difluoropropoxy)-3-pyridyl]methanesulfonamide (112 mg,77%) as a yellow solid.

Step 5:N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2-difluoropropoxy)pyridin-3-yl]methanesulforamide

To a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,50 mg, 0.17 mmol) andN-[5-(2,2-difluoropropoxy)-3-pyridyl]methanesuffonamide (49 mg, 0.19mmol) in N,N-dimethylformamide (1 mL) was added sodium bicarbonate (35mg, 0.42 mmol). The mixture was stirred at 20° C. for 16 h and filtered.The filtrate was concentrated to dryness under reduced pressure. Theresidue was purified by RP-HPLC (35 to 65% acetonitrile in water and0.225% formic acid) to affordN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2-difluoropropoxy)pyridin-3-yl]methanesulfonamide(26 mg, 32%) as a yellow oil.

Preparation ofN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethyl)pyridin-3-yl]ethane-1-sulfonamide(I-227);N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide(I-207) andN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide(I-208)

Step 1: 1-(5-bromo-3-pyridyl)ethanol

To a solution of 1-(5-bromo-3-pyridyl)ethanone (3.0 g, 15.00 mmol) inmethanol (30 mL) was added sodium borohydride (1.1 g, 30.00 mmol) insmall portions. The mixture was stirred at 20° C. for 16 h andconcentrated under reduced pressure. The residue was diluted withsaturated aqueous ammonium chloride (10 mL) and water (30 mL), andextracted with ethyl acetate (3×50 mL). The combined organic extractswere dried and concentrated. The residue was purified by flash columnchromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate inpetroleum ether) to afford 1-(5-bromo-3-pyridyl)ethanol (2.80 g, 92%) ascolorless oil.

Step 2: 3-bromo-5-(1-fluoroethyl)pyridine

To a solution of 1-(5-bromo-3-pyridyl)ethanol (2.6 g, 12.87 mmol) indichloromethane (2 mL) was added bis(2-methoxyethyl)aminosulfurtrifluoride (2.9 g, 13.06 mmol) dropwise at 0° C. under nitrogenatmosphere. The mixture was stirred at 20° C. for 0.5 h and quenched byaddition of saturated aqueous sodium bicarbonate (40 mL). The mixturewas then extracted with ethyl acetate (3×40 mL). The combined organicextracts were dried and concentrated under reduced pressure. The residuewas purified by flash column chromatography (silica gel, 100-200 mesh,0-5% ethyl acetate in petroleum ether) to afford3-bromo-5-(1-fluoroethyl)pyridine (1.78 g, 65%) as a light yellow oil.

Step 3: N-[5-(1-fluoroethyl)-3-pyridyl]-1,1-diphenyl-methanimine

To a solution of 3-bromo-5-(1-fluoroethyl)pyridine (1.8 g, 8.72 mmol)and diphenylmethanimine (1.7 g, 9.60 mmol) in toluene (30 mL) was added(R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthalene (543 mg, 0.87mmol), sodium tert-butoxide (838 mg, 8.72 mmol) andtris(dibenzylideneacetone)dipalladium (399 mg, 0.44 mmol) at 20° C.under nitrogen atmosphere. The mixture was stirred at 80° C. for 16 hand concentrated under reduced pressure. The residue was purified byflash column chromatography (silica gel, 100-200 mesh, 0-10% ethylacetate in petroleum ether) to affordN-[5-(1-fluoroethyl)-3-pyridyl]-1,1-diphenyl-methanimine (2.19 g, 73%)as a light yellow oil.

Step 4: 5-(1-fluoroethyl)pyridin-3-amine

To a solution ofN-[5-(1-fluoroethyl)-3-pyridyl]-1,1-diphenyl-methanimine (500 mg, 1.64mmol) in tetrahydrofuran (6 mL) was added hydrochloric acid (1 M, 2.0mL, 2.0 mmol) at 20° C. The mixture was stirred at 20° C. for 2 h anddiluted with water (10 mL). The solution was washed with ethyl acetate(3×10 mL). The aqueous layer was adjusted to pH=8 by addition of aqueoussodium hydroxide (1 M) and extracted with dichloromethane (3×10 mL). Thecombined organic extracts were dried and concentrated under reducedpressure to afford crude 5-(1-fluoroethyl)pyridin-3-amine (200 mg, 86%)as light yellow oil.

Step 5: N-[5-(1-fluoroethyl)-3-pyridyl]ethanesufonamide

To a solution of 5-(1-fluoroethyl)pyridin-3-amine (200 mg, 1.43 mmol) inpyridine (5 mL) was added ethanesulfonyl chloride (22.0 mg, 1.71 mmol)at 20° C. The mixture was stirred at 20° C. for 16 h and concentratedunder reduced pressure. The residue was purified by preparative TLC(dichloromethane:methanol=10:1) to affordN-[5-(1-fluoroethyl)-3-pyridyl]ethanesulfonamide (236 mg, 71%) as awhite solid.

Step 6:N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethy)pyridin-3-yl]ethane-1-sulfonamideandN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamideandN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide

To a solution of N-[5-(1-fluoroethyl)-3-pyridyl]ethanesulfonamide (206mg, 0.89 mmol) in N,N-dimethylformamide (4.5 mL) was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (263mg, 0.89 mmol) and sodium bicarbonate (22.4 mg, 2.66 mmol) at 20° C. Themixture was stirred at 20° C. for 16 h and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by RP-HPLC(0 to 40% acetonitrile in water and 0.225% formic acid) to affordN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethyl)pyridin-3-yl]ethane-1-sulfonamide(101.2 mg, 25%) as a brown oil.

The above racemate (98 mg, 0.22 mmol) was further separated by SFC toafford arbitrarily assigned:

N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide(Peak 1, retention time=2.597 min) (11.1 mg, 11%) as a light yellow oil.

N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}ethane-1-sulfonamide(Peak 2, retention time=2.689 min) (15.2 mg 15%) as a light yellow oil.

SFC condition: Column: (S,S)-Whelk-0-3 50iA4.6 mm I.D. 1.8 um, Mobilephase: A: CO₂ B: ethanol (0.05% DEA); Gradient: from 5% to 40% of B in4.5 min and hold 40% for 2.5 min, then 5% of B for 1.5 min; Flow rate:2.8 mL/min, Column temperature: 40° C.

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-phenylcyclopropyl)ethanesulfoamide(Compound I-20).

Step 1: Preparation of N-(1-phenylcyclopropyl)ethanesulfonamide.

To a vial containing the commercially available1-phenylcyclopropan-1-amine (200 mg, 1.50 mmol) in DCM (1 mL) at ambienttemperature, was added pyridine (143 mg, 1.80 mmol) and thenethanesulfonyi chloride (232 mg, 1.80 mmol). The mixture was stirred atambient temperature for 18 h. Quenched with 1 N HCl, the reactionmixture was extracted with EtOAc. The organic layer was washed withwater, dried (Na₂SO₄), filtered and concentrated. The resulting residuewas purified by chromatography (Silica gel, EtOAc/hexane, 0:1 to 1:1) toafford the title compound as an oil, 95 mg (28.1%).

Step 2:N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-phenylcyclopropyl)ethanesulfonamide

To a vial containing NaH (7.29 mg, 60 wt. % in mineral oil, 0.18 mmol)in DMF at 0° C. was added a solution ofN-(1-phenylcyclopropyl)ethanesulfonamide from Step 1 in DMF (45 mg, 0.20mmol) dropwise. After the reaction was stirred at ambient temperaturefor 10 min, the mixture was added dropwise to a cold solution of2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)1,3,4-oxadiazole(4a, 40 mg, 0.14 mmol) in DMF in an ice bath. The reaction mixture wasthen stirred and warmed up to ambient temperature for 4 h, then quenchedwith saturated aqueous NH₄Cl and added EtOAc, the organic layer wasdried (Na₂SO₄), filtered and concentrated. The resulting residue waspurified by chromatography (Silica gel, EtOAc/hexane, 0:1 to 3:2) toafford a light brow solid, 22 mg (37%).

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-(difluoromethyl)-1H-pyrazol-4-yl)ethanesulfonamide(Compound I-48).

Step 1: N-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide

To a solution of 1-(difluoromethyl)pyrazol-4-amine (100 mg, 0.75 mmol)in pyridine (2 mL) was added ethanesulfonyl chloride (116 mg, 0.90mmol). The mixture was stirred at 20° C. for 16 hours and concentratedunder reduced pressure. The residue was purified by RP-TLC(dichloromethane:methanol=20:1) to affordN-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide (100 mg, 59%) as ared solid.

Step 2:N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-(difluoromethyl)-1H-pyrazol-4-yl)ethanesulfonamide(Compound I-48)

To a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,17 mg, 0.06 mmol) in N,N-dimethylformamide (0.2 mL) was added sodiumbicarbonate (15 mg, 0.17 mmol) andN-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide (19 mg, 0.08 mmol).The mixture was stirred at 20° C. for 16 hours and filtered. Thefiltrate was concentrated to dryness under reduced pressure. The residuewas purified by RP-HPLC (22-55% acetonitrile in water and 0.225% formicacid) to affordN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[1-(difluoromethyl)pyrazol-4-yl]ethanesulfonamide(14.1 mg, 56%) as a yellow solid.

Preparation ofN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1H-imidazol-5-yl)ethane-1-sulfonamide(I-235)

Step 1: trimethyl-[2-[(5-nitroimidazol-1-yl)methoxy]ethyl]silane

To a solution of 5-nitro-1H-imidazole (2.0 g, 18 mmol) intetrahydrofuran (20 mL) was added sodium hydride (60%, 1.1 g, 28 mmol)at 0° C. under nitrogen atmosphere. The mixture was stirred at 20° C.for 1 h and then 2-(chloromethoxy)ethyl-trimethyl-silane (3.5 g, 21mmol) was added. The resulting mixture was stirred at 20° C. for 16 hand quenched by addition of water (5 mL). The solution was extractedwith ethyl acetate (100 mL). The organic extract was washed with brine(100 mL), dried over sodium sulphate and concentrated to dryness underreduced pressure. The residue was purified by flash columnchromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate inpetroleum ether) to affordtrimethyl-[2-[(5-nitroimidazol-1-yl)methoxy]ethyl]silane (3.75 g. 83%)as a yellow solid.

Step 2.: 3-(2-trimethylsilylethoxymethyl)imidazol-4-amine

To a solution oftrimethyl-[2-[(5-nitroimidazol-1-yl)methoxy]ethyl]silane (1.0 g, 4 mmol)in tetrahydrofuran (10 mL) was added palladium (10% on carbon, 437 mg,0.41 mmol). The mixture was hydrogenated (15 psi) at 20° C. for 1 h andfiltered. The filtrate was concentrated to dryness under reducedpressure to afford crude3-(2-trimethylsilylethoxymethyl)imidazol-4-amine (800 mg, crude) as ablack brown oil used as is in the next step.

Step 3:N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide

To a solution of 3-(2-trimethylsilylethoxymethyl)imidazol-4-amine (800mg, 3.75 mmol) in tetrahydrofuran (15 mL) was added ethanesulfonylchloride (579 mg, 4.50 mmol) and pyridine (890 mg, 11.25 mmol). Themixture was stirred at 20° C. for 2 h and concentrated to dryness underreduced pressure. The residue was purified by preparative TLC(dichloromethane:methanol=10:1) to affordN-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide (53mg, 4%) as a light yellow solid.

Step 4:N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]ithiazol-2-yl]methyl]-N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide

To a solution ofN-[3-(2-trimetylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide (50mg, 0.16 mmol) in N,N-dimethylformamide (2 mL) was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,80 mg, 0.27 mmol) and sodium bicarbonate (34 mg, 0.41 mmol). The mixturewas stirred at 20° C. for 2 h and filtered. The filtrate wasconcentrated to dryness under reduced pressure. The residue was purifiedby preparative TLC (dichloromethane:methanol=20:1) to affordN-[[5-[45-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide(65 mg, 46%) as a yellow solid.

Step 5:N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1H-imidazol-5-yl)ethane-1-sulfonamide

To a solution ofN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]ethanesulfonamide(59 mg, 0.11 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (6 mL) was addedtrifluoroacetic acid (129 mg, 1.13 mmol). The mixture was stirred at 20°C. for 16 h and concentrated to dryness under reduced pressure. Theresidue was purified by RP-HPLC (20 to 50% acetonitrile in water and0.225% formic acid) to affordN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1H-imidazol-5-yl)ethane-1-sulfonamide(9.7 mg, 22%) as a light yellow solid

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(difluoromethyl)pyridin-3-yl)ethanesulfonamide(Compound I-60).

Step 1: 3-bromo-5-(difluoromethyl)pyridine

To a solution of 5-bromopyridine-3-carbaldehyde (500 mg, 2.7 mmol) indichloromethane (4 mL) was added diethylaminosulphur trifluoride (867mg, 5.38 mmol) at 0° C. under nitrogen atmosphere. Then the mixture wasallowed to warm to 20° C. and stirred for 2 hours. After quenched byaddition of water (50 mL) carefully, the reaction was extracted withethyl acetate (50 mL×3). The combined organic layers were dried oversodium sulphate and concentrated to dryness under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-50% ethyl acetate in petroleum ether) to give3-bromo-5-(difluoromethyl)pyridine (370 mg, 66%) as a yellow solid.

Step 2: N-[5-(difluoromethyl)-3-pyridyl]-1,1-diphenyl-methanimine

A mixture of 3-bromo-5-(difluoromethyl)pyridine (300 mg, 1.44 mmol),diphenylmethanimine (262 mg, 1.44 mmol), BINAP (90 mg, 0.14 mmol),Pd₂(dba)₃ (66 mg, 0.07 mmol) and sodium tert-butoxide (139 mg, 1.44mmol) in toluene (2 mL) was stirred at 80° C. for 16 hours undernitrogen protection. The reaction was quenched by addition of water (50mL) and extracted with ethyl acetate (50 mL×3). The combined organiclayers were dried over sodium sulphate and concentrated to dryness underreduced pressure. The residue was purified by column chromatography(silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) toafford N-[5-(difluoromethyl)-3-pyridyl]-1,1-diphenyl-methanimine (300mg, 68%) as a yellow solid.

Step 3: 5-(difluoromethyl)pyridin-3-amine

A solution of N-[5-(difluoromethyl)-3-pyridyl]-1,1-diphenyl-methanimine(300 mg, 0.97 mmol) in tetrahydrofuran (5 mL) and hydrochloric acid (1Min water, 2 mL) was stirred at 20° C. for 2 hours. The reaction mixturewas diluted with water (50 mL) and then washed with ethyl acetate (50mL×2). The aqueous layer was adjusted to pH=11 by addition of aqueoussodium hydroxide (1.0 M) and extracted with dichloromethane (50 mL×2).The combined organic layers were dried over sodium sulphate andconcentrated to dryness under reduced pressure to afford crude5-(difluoromethyl)pyridin-3-amine (112 mg, 80%) as a yellow solid.

Step 4:N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(difluoromethyl)pyridin-3-yl)ethanesulfonamide(Compound I-60)

Prepared from the2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole asdescribed above for I-6. The crude product was purified by RP-HPLC(30-60% acetonitrile in water and 0.05% ammonia hydroxide) to affordN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(difluoromethyl)-3-pyridyl]ethanesulfonamide(4.9 mg, 16%) as a white solid.

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)ethanesulfonamide(Compound I-81).

Step 1: N-(5-fluoropyrimidin-2-yl)ethanesulfonamide

A mixture of 2-chloro-5-fluoro-pyrimidine (150 mg, 1.13 mmol),ethanesulfonamide (148 mg, 1.36 mmol) and cesium carbonate (922 mg, 2.83mmol) in dimethyl sulfoxide (3 mL) was stirred at 100° C. for 16 hoursand filtered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by RP-HPLC (10-40% acetonitrile inwater and 0.225% formic acid) to affordN-(5-fluoropyrimidin-2-yl)ethanesulfonamide (63 mg, 27%) as a whitesolid.

Step 2:N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyrimidin-2-yl)ethanesulfonamide(Compound I-81)

A mixture of N-(5-fluoropyrimidin-2-yl)ethanesulfonamide (12 mg, 0.06mmol),2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,15 mg, 0.05 mmol) and potassium carbonate (21 mg, 0.15 mmol) inN,N-dimethylformamide (1 mL) was stirred at 20° C. for 1 hour andfiltered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by RP-HPLC (44-74% acetonitrile inwater and 0.225% formic acid) to affordN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-(5-fluoropyrimidin-2-yl)ethanesulfonamide(9.9 mg, 46%) as a yellow solid.

Preparation ofN-(pyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide(I-119)

Step 1: 2-(2-metylthiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole

To a solution of 2-methylthiazole-5-carbohydrazide (3.5 g, 22.27 mmol)in N,N-dimethylformamide (50 mL) was added trifluoroacetic anhydride(18.7 g, 89.06 mmol) and triethylamine (22.5 g, 222.66 mmol). Afterstirring at 70° C. for 2 h, the reaction mixture was diluted with ethylacetate (100 mL), washed with brine (3×50 mL), dried and concentrated todryness under reduced pressure. The residue was purified by flash columnchromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate inpetroleum ether) to afford2-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (2.2 g,39%) as a yellow solid.

Step 2:2-(2-(bromomethyl)thiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole

To a solution of2-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (2.3 g,9.78 mmol) in 1,2-dichloroethane (100 mL) was added N-bromosuccinimide(2.6 g, 14.67 mmol) and azodiisobutyronitrile;azobisisobutyronitrile(161 mg, 0.98 mmol). The mixture was stirred at 80° C. for 12 h andconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography (silica gel, 100-200 mesh, 0-20% ethylacetate in petroleum ether) to afford2-[2-(bromomethyl)thiazol-5-yl]-5-(trifluoromethyl)-1,3,4-oxadiazole(1.11 g, 35%) as a yellow solid.

Step 3:N-(pyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide

To a solution of N-(3-pyridyl)ethanesulfonamide (28 mg, 0.15 mmol) inN,N-dimethylformamide (1 mL) was added sodium bicarbonate (32 mg, 0.38mmol) and2-[2-(bromomethyl)thiazol-5-yl]-5-(trifluoromethyl)-1,3,4-oxadiazole(4b, 40 mg, 0,13 mmol). The mixture was stirred at 20° C. for 2 h andfiltered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by RP-HPLC (45 to 75% acetonitrile inwater and 0.225% formic acid) to affordN-(pyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide(7.0 mg, 13%) as a yellow solid

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)ethanesulfonamide(Compound I-102)

Step 1:[1-(6-bromo-3-pyridyl)-1-methyl-ethoxy]-tert-butyl-dimethyl-silane

To a solution of 2-(6-bromo-3-pyridyl)propan-2-ol (70 mg, 0.32 mmol) indichloromethane (1 mL) was added 2,6-lutidine (69 mg, 0.65 mmol) and[tert-butyl (dimethyl)silyl]trifluoromethanesulfonate (128 mg, 0.49mmol). After stirred at 20° C. for 2 hours, the reaction was quenched byaddition of water (10 mL) and ethyl acetate (30 mL). The separatedorganic layer was dried over sodium sulphate and concentrated to drynessunder reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate inpetroleum ether) to afford[1-(6-bromo-3-pyridyl)-1-methyl-ethoxy]-tert-butyl-dimethyl-silane (70mg, 65%) as colorless oil.

Step 2:N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]ethanesulfonamide

To a solution of[1-(6-bromo-3-pyridyl)-1-methyl-ethoxy]-tert-butyl-dimethyl-silane (160mg, 0.48 mmol) in 1,4-dioxane (6 mL) was added ethanesulfonatnide (159mg, 1.45 mmol), cesium carbonate (789 mg, 2.42 mmol), Xantphos (56 mg,0.10 mmol) and Pd₂(dba)₃ (44 mg, 0.05 mmol). The reaction mixture wasstirred at 110° C. for 16 hours under nitrogen atmosphere and filtered.The filtrate was concentrated to dryness under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-10% methanol in dichloromethane) to afford N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]ethanesulfonamide (71 mg,38%) as a yellow solid.

Step 3:N-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide

To a solution ofN-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]ethanesulfonamide(68 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added2-[2-(bromornethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole(4a, 73 mg, 0.25 mmol) and sodium bicarbonate (48 mg, 0.57 mmol). Thereaction mixture was stirred at 20° C. for 6 hours and filtered. Thefiltrate was concentrated to dryness under reduced pressure. The residuewas purified by column chromatography (silica gel, 100-200 mesh, 0-25%ethyl acetate in petroleum ether) to affordN-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide(13 mg, 11%) as yellow oil.

Step 4:N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)ethanesulfonamide(Compound I-102)

To a solution ofN-[5-[1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-2-pyridyl]-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]ethanesulfonamide(10 mg, 0.02 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (2 mL) was addedtrifluoroacetic acid (154 mg, 1.35 mmol). The reaction mixture wasstirred at 20° C. for 2 hours and concentrated under reduced pressure.The residue was purified by RP-HPLC (35-65% acetonitrile in water and0.225% formic acid) to affordN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]ethanesulfonamide(5.8 mg, 72%) as a white solid.

Preparation of2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide(I-219)

Step 1: methyl 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoate

To a solution of 5-methylpyridin-3-amine (400 mg, 3.70 mmol) in pyridine(6 mL) was added methyl 3-chlorosulfonylpropanoate (966 mg, 5.18 mmol).The mixture was stirred at 20° C. for 16 h and concentrated underreduced pressure. The residue was purified by preparative TLC(dichloromethane:methanol=10:1) to afford methyl3-[(5-methyl-3-pyridyl)sulfamoyl]propanoate (440 mg, 40%) as a lightyellow solid.

Step 2: 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid

To a solution of methyl 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoate (390mg, 1.51 mmol) in methanol (6 mL) was added sodium hydroxide (181 mg,4.53 mmol) in water (2 mL). The mixture was stirred at 20° C. for 3 hand concentrated under reduced pressure. The residue was adjusted topH=3 by addition of hydrochloric acid (1 M) and filtered to give crude3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid (213 mg, crude) as alight yellow solid.

Step 3: 3-[(5-methyl-3-pyridyl)sulfamoyl]propanamide

To a solution of 3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid (203mg, 0.83 mmol) in N,N-dimethylformamide (6 mL) was added2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (632 mg, 1.66 mmol), ammonium chloride (178 mg,3.32 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.1 g, 8.31 mmol). Themixture was stirred at 20° C. for 16 h and concentrated under reducedpressure. The residue was purified by RP-HPLC (0 to 15% acetonitrile inwater and 0.05% NH₃H₂O+10 mM NH₄HCO₃) to afford3-[(5-methyl-3-pyridyl)sulfamoyl]propanoic acid (213 mg, crude) as alight yellow solid.

Step 4:3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl-(5-methyl-3-pyridyl)sulfamoyl]propanamide

To a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,43 mg, 0.14 mmol) in N,N-dimethylformamide (2 mL) was added3-[(5-methyl-3-pyridyl)sulfamoyl]propanamide (42 mg, 0.17 mmol) andsodium bicarbonate (36 mg, 0.43 mmol). The mixture was stirred at 20° C.for 16 h and filtered. The filtrate was concentrated and the residue waspurified by preparative TLC (dichloromethane:methanol=10:1) to afford3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl-(5-methyl-3-pyridyl)sulfamoyl]propanamide(12 mg, 15%) as a yellow solid.

Step 5:2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide

To a solution of3-(N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-methylpyridin-3-yl)sulfamoyl)propanamide(12 mg, 0.03 mmol) in dichloromethane (2 mL) was added Burgess reagent(37 mg, 0.16 mmol) at 0° C. The mixture was stirred at 20° C. for 2 hand filtered. The filtrate was concentrated under reduced pressure andthe residue was purified by RP-HPLC (16 to 56% acetonitrile in water and0.225% formic acid) to afford2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide(1.4 mg, 12%) as a light yellow solid.

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethane-1-sulfonamide(I-174)

Step 1: N-(3-pyridyl)ethenesulfonamide

To a solution of ethenesulfonyl chloride (70 mg, 0.55 mmol) andpyridin-3-amine (52 mg, 0.55 mmol) in dichloromethane (2 mL) was addedtriethylamine (62 mg, 0.61 mmol) at −78° C. under nitrogen atmosphere.The mixture was stirred at −78° C. for 0.5 h and then at 0° C. for 2 h.The reaction mixture was to be used directly in next step withoutpurification.

Step 2:2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(3-pyridyl)ethanesulfonamide

To above solution of N-(3-pyridyl)ethenesulfonamide in dichloromethane(2 mL) was added 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrolehydrochloride (69 mg, 0.46 mmol) and triethylamine (71 mg, 0.71 mmol) at25° C. under nitrogen atmosphere. The mixture was stirred at 25° C. for16 h and then concentrated under reduced pressure. The residue waspurified by preparative TLC (dichloromethane:methanol=10:1) to afford2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(3-pyridyl)ethanesulfonamide(30 mg, 29%) as a light yellow oil.

Step 3:N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methy)-N-(pyridin-3-yl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethane-1-sulfonamide

To a solution of2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-N-(3-pyridyl)ethanesulfonamide(25 mg, 0.08 mmol) and2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,25 mg, 0.08 mmol) in N,N-dimethylformamide (0.3 mL) was added sodiumbicarbonate (21 mg, 0.25 mmol). The mixture was stirred at 35° C. for 3h and filtered. The filtrated was concentrated to dryness under reducedpressure. The residue was purified by RP-HPLC (0 to 40% acetonitrile inwater and 0.225% formic acid) to affordN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethane-1-sulfonamide(3.1 mg, 7%) as a light yellow oil.

Preparation ofN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(1,4-oxazepan-4-yl)ethane-1-sulfonamide(I-186)

Step 1: N-(5-fluoro-3-pyridyl)ethenesulfonamide

To a solution of ethenesulfonyl chloride (100 mg, 0.79 mmol) indichloromethane (1 mL) was added 5-fluoropyridin-3-amine (88 mg, 0.79mmol) and triethylamine (159 mg, 1.58 mmol) at −78° C. The mixture waswarmed to 20° C. and stirred for 30 minutes. The reaction mixture was tobe used directly in next step without further treatment.

Step 2: N-(5-fluoro-3-pyridyl)-2-(1,4-oxazepan-4-yl)ethanesulfonamide

To the above solution was added 1,4-oxazepane (60 mg, 0.59 mmol) andtriethyiamine (50 mg, 0.49 mmol) at 0° C. The mixture was stirred at 20°C. for 2 h and concentrated to dryness under reduced pressure. Theresidue was purified by preparative TLC (dichloromethane:methanol=20:1)to afford N-(5-fluoro-3-pyridyl)-2-(1,4-oxazepane-4-yl)ethanesulfonamide(57 mg, 37%) as a colorless oil.

Step 3:N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(1,4-oxazepan-4-yl)ethane-1-sulfonamide

To a solution ofN-(5-fluoro-3-pyridyl)-2-(1,4-oxazepan-4-yl)ethanesulfonamide (57 mg,0.18 mmol) in N,N-dimethylformamide (1 mL) was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,55 mg, 0.19 mmol) and sodium bicarbonate (47 mg, 0.56 mmol). The mixturewas stirred at 20° C. for 2 h and filtered. The filtrate wasconcentrated to dryness under reduced pressure and the residue waspurified by RP-HPLC (0 to 40% acetonitrile in water and 0.225% formicacid) to affordN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(1,4-oxazepan-4-yl)ethane-1-sulfonamide(12.6 mg, 12%) as a yellow oil.

Preparation ofN-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)butane-2-sulfonamide(I-177)

Step 1: sec-butyl sulfonyloxysodium

To a solution of 2-bromobutane (5.0 g, 36.49 mmol) in water (50 mL) wasadded sodium sulphate (5.1 g, 40.14 mmol). The mixture was stirred at100° C. for 16 h and filtered. The filtrate was concentrated underreduced pressure. The residue was triturated with chloroform andfiltered to give crude sec-butylsulfonyloxysodium (8.8 g, crude) as awhite solid used in the next step as is.

Step 2: butane-2-sulfonyl chloride

To a solution of sec-butylsulfonyloxysodium (8 g, 49.95 mmol) in thionylchloride (25 mL) was added N,N-dimethylformamide (233 mg, 3.19 mmol).The mixture was heated at 100° C. for 3 h and concentrated under reducedpressure. The residue was triturated with chloroform and filtered. Thefiltrate was concentrated under reduced pressure to affordbutane-2-sulfonyl chloride (3 g, crude) as a yellow oil used in the nextstep as is.

Step 3: N-[5-(difluoromethoxy)-3-pyridyl]butane-2-sulfonamide

To a solution of 5-(difluoromethoxy)pyridin-3-amine (2 g, 12.49 mmol) indichloromethane (20 mL) was added butane-2-sulfonyl chloride (2.74 g,17.49 mmol) and pyridine (2.96 g, 37.47 mmol). After stirring at 25° C.for 3 h, the mixture was concentrated under reduced pressure. Theresidue was purified by RP-HPLC (25 to 70% acetonitrile in water and0.225% formic acid) to affordN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[2-(trifluoromethyl)-4-pyridyl]ethanesulfonamide(790 mg, 20%) as a white solid.

Step 4:N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[45-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)butane-2-sulfonamide

To a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,349 mg, 1.18 mmol) in acetone (3 mL) was addedN-[5-(difluoromethoxy)-3-pyridyl]butane-2-sulfonamide (300 mg, 1.07mmol) and potassium carbonate (444 mg, 3.21 mmol). The mixture wasstirred at 25° C. for 1.5 h and filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by RP-HPLC (40 to 70%acetonitrile in water and 0.1% trifluoroacetic acid) to affordN-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)butane-2-sulfonamide318 (268.4 mg, 51%) as a yellow solid.

Preparation ofN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide(I-267)

Step 1: 5-bromo-3-(trifluoromethoxy)pyridin-2-amine

To a solution of 3-(trifluoromethoxy)pyridin-2-amine (900 mg, 5.05 mmol)in dichloromethane (10 mL) was added N-bromosuccinimide (1.4 g, 7.58mmol). After stirring at 25° C. for 0.5 hour, the reaction mixture wasfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-6% ethyl acetate in petroleum ether) to afford5-bromo-3-(trifluoromethoxy)pyridin-2-amine (1.14 g, 84%) as a brownsolid.

Step 2: 5-bromo-2-chloro-3-(trifluoromethoxy)pyridine

To a solution of 5-bromo-3-(trifluoromethoxy)pyridin-2-amine (1.1 g,4.44 mmol) in dichloromethane (4 mL) was added chlorotrimethylsilane(4.3 g, 39.92 mmol). After stirring at 25° C. for 0.5 hour, isopentylnitrite (1.6 g, 13.31 mmol) was added dropwise. After stirring at 25° C.for 2 hours, the reaction mixture was filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-2%, ethyl acetate inpetroleum ether) to afford 5-bromo-2-chloro-3-(trifluoromethoxy)pyridine(955 mg, 71%) as colorless oil.

Step 3: N-[6-chloro-5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide

To a solution of ethanesulfonamide (79 mg, 0.72 mmol) and5-bromo-2-chloro-3-(trifluoromethoxy)pyridine (200 mg, 0.72 mmol) in1,4-dioxane (5 mL) was added Xantphos Pd G3 (69 mg, 0.07 mmol) andcesium carbonate (589 mg, 1.81 mmol). After stirring at 110° C. for 16hours under nitrogen atmosphere, the reaction mixture was filtered. Thefiltrate was concentrated under reduced pressure and the residue waspurified by column chromatography (silica gel, 100-200 mesh, 0-15%methanol in dichloromethane) to affordN-[6-chloro-5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (38 mg,16%) as yellow oil.

Step 4: N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide

To a solution ofN-[6-chloro-5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (38 mg,0.12 mmol) in methanol (1 mL) was added palladium (13 mg, 0.01 mmol, 10%on carbon). After stirring at 25° C. under hydrogen atmosphere (15 psi)for 2 hours, the reaction mixture was filtered. The filtrate wasconcentrated under reduced pressure to afford crudeN-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (30 mg, crude) as ayellow solid.

Step 5:N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide

To a solution of N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide (20mg, 0.07 mmol) and2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,20 mg, 0.07 mmol) in acetone (1 mL) was added potassium carbonate (28mg, 0.20 mmol). After stirring at 25° C. for 1 hour, the reactionmixture was filtered. The filtrate was concentrated under reducedpressure. The residue was purified by RP-HPLC (35 to 65% acetonitrile inwater and 0.225% formic acid) to affordN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-[5-(trifluoromethoxy)-3-pyridyl]ethanesulfonamide(8.5 mg, 25%) as a yellow solid.

Preparation ofN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}ethane-1-sulfonamide(I-231)

Step 1: methyl5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazole-3-carboxylate

To a solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (2.0 g, 11.69mmol) in N-methyl-2-pyrrolidone (10 mL) was added2-(2-bromoethoxy)tetrahydropyran (2.0 g, 9.35 mmol) and potassiumcarbonate (1.6 g, 11.69 mmol). After stirring at 80° C. for 16 h, thereaction mixture was diluted with water (30 mL) and ethyl acetate (50mL). The separated organic layer was dried over sodium sulphate andconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography (silica gel, 100-200 mesh, 0-25% ethylacetate in petroleum ether) to afford methyl5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazole-3-carboxylate (2.2 g,63%) as yellow oil.

Step 2: [5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]methanol

To a solution of methyl5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazole-3-carboxylate (2.2 g,7.35 mmol) in tetrahydrofuran (30 mL) was added lithium borohydride (240mg, 11.03 mmol) at 0° C. After stirring at 20° C. for 3 h, the reactionwas quenched by addition of methanol (10 mL). The mixture was dilutedwith ethyl acetate (40 mL), washed with brine (40 mL), dried over sodiumsulphate and concentrated to dryness under reduced pressure. The residuewas purified by flash column chromatography (silica gel, 100-200 mesh,0-50% ethyl acetate in petroleum ether) to afford[5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]methanol (1.4 g,70%) as a yellow oil.

Step 3: 2-[5-(bromomethyl)-3-nitro-pyrazol-1-yl]ethanol

To a solution of[5-nitro-2-(2-tetrahydropyran-2-yloxyethyl)pyrazol-3-yl]methanol (1.4 g,5.16 mmol) in tetrahydrofuran (10 mL) was added pyridine (408 mg, 5.16mmol), tetrabromomethane (3.4 g, 10.32 mmol) and triphenylphosphine (2.7g, 10.32 mmol) at 0° C. The mixture was stirred at 20° C. for 17 h andfiltered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography(silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether),followed by preparative TLC (petroleum ether:ethyl acetate=1:1) toafford 2-[5-(bromomethyl)-3-nitro-pyrazol-1-yl]ethanol (180 mg, 14%) asa white solid.

Step 4: 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

To a solution of 2-[5-(bromomethyl)-3-nitro-pyrazol-1-yl]ethanol (140mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (60%,25 mg, 0.62 mmol) under nitrogen atmosphere. After stirring at 20° C.for 4 h, the reaction mixture was quenched by addition of water (10 mL)and extracted with ethyl acetate (30 mL). The organic extract was driedover sodium sulphate and concentrated to dryness under reduced pressure.The residue was purified by preparative TLC (petroleum ether:ethylacetate=1:1) to afford2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (34 mg, 33%) as awhite solid.

Step 5: 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine

To a solution of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (24mg, 0.1 mmol) in ethanol (2.5 mL) and water (1 mL) was added iron (48mg, 0.85 mmol) and ammonium chloride (91 mg, 1.70 mmol). The mixture wasstirred at 80° C. for 4 h and filtered. The filtrate was concentrated todryness under reduced pressure. The residue was diluted withdichloromethane (15 mL), washed with brine (20 mL), dried over sodiumsulphate and concentrated to dryness under reduced pressure to afford6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (13 mg, 66%) as ayellow solid.

Step 6:N-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)ethanesulfonamide

To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (22mg, 0.16 mmol) in pyridine (0.5 mL) was added ethanesulfonyl chloride(24 mg, 0.19 mmol) at 0° C. The mixture was stirred at 20° C. for 2 hand filtered. The filtrate was concentrated to dryness under reducedpressure. The residue was purified by preparative TLC(dichloromethane:methanol=10:1) to affordN-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)ethanesulfonamide (24mg, 53%) as a white solid.

Step 7:N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}ethane-1-sulfonamide

To a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,25 mg, 0.08 mmol) in N,N-dimethylformamide (0.5 mL) was addedN-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)ethamesulfonamide (21mg, 0.09 mmol) and sodium bicarbonate (21 mg, 0.25 mmol). The mixturewas stirred at 25° C. for 2 h and filtered. The filtrate wasconcentrated to dryness under reduced pressure. The residue was purifiedby RP-HPLC (30 to 60% acetonitrile in water and 0.225% formic acid) toaffordN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}ethane-1-sulfonamide(10.9 mg, 28%) as a yellow oil.

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-3-yl)-1′-benzyl-1′-methylamino-sulfonamide(Compound I-29).

Step 1: N-Benzyl-N-methylsulfamoyl chloride

To a solution of sulfuryl chloride (1.11 g, 8.25 mmol) indichloromethane (10 mL) at −10° C. is added N-methyl-N-benzylamine (1.00g, 8.25 mmol). The cooling bath was removed after 30 min. and thereaction mixture was kept stirring for 5 h. Washed with water, theorganic layer was dried (Na₂SO₄), filtered and concentrated. Theresulting crude residue was directly used in the next step.

Step 2: N-Benzyl-N-methyl-[(5-fluoropyridin-3-yl)amino]sulfonamide

Half of the above crude material was mixed with 5-fluoro-3-pyridin-amine(196 mg, 0.89 mmol) and pyridine (106 mg, 1.34 mmol) in dichloromethaneat ambient temperature. After stirred for 2 h, the reaction was quenchedwith sat. NH₄Cl. The organic residue was purified by chromatography(Silica gel, DCM/EtOAc, 1:0 to 1:1) to afford a white solid (25 mg,9.5%). LC-MS: m/z [M+H]⁺296.

Step 3:N-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-3-yl)-1′-benzyl-1′-methylamino-sulfonamide

The title compound was synthesized by following the same experimentalprocedure as described in the preparation ofN-((5-(5-difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl-N-(1-phenylcyclopropoyl)ethanesulfonamide(I-20), employing the aboveN-benzyl-N-methyl-[(5-fluoropyridin-3-yl)amino]sulfonamide instead (36%yield).

The methods disclosed above in Example 4 were also used to prepare thefollowing compounds: I-2, I-3, I-4, I-5, I-9, I-10, I-13, I-14, I-15,I-16, I-17, I-22, I-23, I-24, I-25, I-27, I-30, I-31, I-32, I-33, I-34,I-35, I-36, I-37, I-38, I-39, I-40, I-46, I-47, I-49, I-50, I-51, I-52,I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-61, I-62, I-63, I-64, I-65,I-66, I-67, I-68, I-69, I-70, I-74, I-75, I-76, I-77, I-78, I-79, I-80,I-87, I-88, I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-97, I-98, I-99,I-100, I-103, I-104, I-405, I-406, I-107, I-108, I-109, I-110, I-111,I-112, I-113, I-114, I-115, I-116, I-117, I-118, I-120, I-121, I-122,I-123, I-125, I-126, I-127, I-128, I-129, I-130, I-131, I-132, I-133,I-134, I-136, I-137, I-138, I-139, I-140, I-141, I-145, I-146, I-148,I-149, I-150, I-151, I-152, I-153, I-155, I-156, I-157, I-158, I-159,I-160, I-161, I-162, I-163, I-164, I-165, I-166, I-167, I-168, I-169,I-170, I-178, I-179, I-180, I-181, I-182, I-183, I-184, I-187, I-188,I-189, I-190, I-191, I-191, I-192, I-193, I-194, I-196, I-197, I-201,I-202, I-203, I-204, I-205, I-206, I-211, I-212, I-213, I-214, I-215,I-216, I-217, I-218, I-220, I-221, I-222, I-223, I-225, I-226, I-228,I-229, I-230, I-232, I-233, I-234, I-236, I-237, I-238, I-239, I-240,I-241, I-242, I-243, I-244, I-265, I-266, and I-268.

Example 5. Synthesis of Amine/Aniline Compounds of Formula (I)

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-(trifluoromethyl)aniline(Compound I-7).

2-[2-(Bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a, 150 mg, 0.51 mmol) wastaken up in DMF (1 ml) with cesium carbonate (330 mg, 0.20 mmol) andthen 3-trifluoromethylaniline (75 μL, 0.60 mmol) was added to it. Thesolution turned dark immediately and was stirred for 16 h at roomtemperature. TLC indicated that the reaction was complete. The solutionwas diluted with EtOAc and then washed with water. The organic layer wasfiltered through MgSO₄ and concentrated. The residue was purified onCombiflash (hexanes/EtOAc gradient) to afford the title compound (75 mg,39%) as an oil.

Preparation of3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(2-methoxyethyl)aniline(I-142)

Step 1: 3-chloro-N-(2-methoxyethyl)aniline

To a solution of 3-chloroaniline (500 mg, 3.92 mmol) in tetrahydrofuran(3 mL) was added sodium hydride (60%, 220 mg, 5.49 mmol) and1-bromo-2-methoxy-ethane (817 mg, 5.88 mmol). The mixture was stirred at70° C. for 2 h and quenched by addition of water (10 mL). The resultingsolution was extracted with ethyl acetate (3×20 mL). The combinedorganic extracts were dried over sodium sulphate and concentrated underreduced pressure. The residue was purified by RP-HPLC (45 to 75%acetonitrile in water and 0.05% ammonium hydroxide+10 mM ammoniumbicarbonate) to afford 3-chloro-N-(2-methoxyethyl)aniline (264 mg, 36%)as a colorless oil.

Step 2:3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(2-methoxyethyl)aniline

To a solution of 3-chloro-N-(2-methoxyethyl)aniline (19 mg, 0.1 mmol) inN,N-dimethylformamide (0.5 mL) was added2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (4a,60 mg, 0.2 mmol) and sodium bicarbonate (26 mg, 0.3 mmol). The mixturewas stirred at 20° C. for 2 h and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by RP-HPLC(20 to 70% acetonitrile in water and 10 mM ammonium bicarbonate) toafford3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(2-methoxyethyl)aniline(13.7 mg, 33%) as a white solid.

The method disclosed in Example 5 was also used to prepare the followingcompounds: I-7, I-45, I-72, I-73, I-124, and I-135.

Preparation ofN-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyridin-3-amine(Compound I-28).

To a 5 mL microwave reaction vial was added2-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole(4a, 60 mg, 0.20 mmol), 3-aminopyridine (57 mg, 0.61 mmol), potassiumiodide (3 mg, 0.02 mmol), potassium carbonate (31 mg, 0.22 mmol), andacetonitrile (0.68 mL). The reaction mixture was stirred at 110° C. for15 min under microwave irradiation. The resulting crude reaction mixturewas filtered through a plug of celite, the plug of celite was washedwith acetonitrile, and the resulting filtrate was concentrated. Theresulting residue was adsorbed onto silica with methanol and purified bycolumn chromatography (0-20% MeOH/DCM) to afford the title compound as alight brown solid (54 mg, 86%).

Example 6. Synthesis of Tertiary Amide Compounds of Formula (I) fromAmines of Example 5

Preparation ofN-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(3-(trifluoromethyl)phenyl)nicotinamide(Compound I-8).

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3-(trifluoromethyl)aniline(I-7, 26 mg, 0.07 mmol) was taken in DMF (1 ml) with nicotinoyl chloridehydrochloride (15 mg, 0.80 mmol) and then diisopropylethylamine (0.04mL, 0.21 mmol) was added to it. The solution was stirred at roomtemperature for 18 h and then at 40° C. for 16 h. TLC indicated that thereaction was completed. The reaction was cooled to room temperature,diluted with EtOAc and then washed with water. The organic layer wascollected, filtered through MgSO₄ and concentrated. The residue waspurified by Combiflash (DCM/methanol gradient) to afford the titlecompound (21 mg, 63%) as a white solid.

The method disclosed in Example 4 was also used to prepare compoundI-175.

Preparation of1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3,3-dimethyl-1-(pyridin-3-yl)urea(Compound I-21).

To a 2 dram vial was addedN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)pyridin-3-amine(I-28, 30 mg, 0.097 mmol), potassium carbonate (40 mg, 0.15 mmol) andacetonitrile (1 mL). To the reaction mixture was added 4-nitrophenylchloroformate (29.3 mg, 0.15 mmol). The reaction mixture was stirred at45° C. for 4 h. To the crude reaction mixture was added a 2 M solutionof dimethylamine in THF (0.24 mL, 0.49 mmol), and the reaction wasstirred at 45° C. for 30 min. The reaction mixture was then filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (0-20% MeOH/DCM) to yield the title compound asan amorphous brown solid (11.4 mg, 31%).

Preparation of Methyl((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)(pyridin-3-yl)carbamate(Compound I-26).

To a 2 dram vial was addedN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)pyridin-3-amine(I-28, 20 mg, 0.065 mmol), potassium carbonate (18 mg, 0.13 mmol) andacetonitrile (0.6 mL). To the reaction mixture was added a 4-nitrophenylchloroformate (19.6 mg, 0.097 mmol). The reaction mixture was stirred at40° C. for 4 h. The reaction mixture was cooled to ambient temperature,and MeOH (1 mL) was added to the reaction mixture. After stirring thereaction mixture for 15 min, the crude reaction mixture was thenfiltered through celite and the celite was washed with MeOH. Thecombined filtrate was concentrated under reduced pressure, adsorbed ontosilica and purified by column chromatography (0-20% EtOAc/hexane) toafford the title compound as an off-white solid (12.6 mg, 53%).

Example 7. Synthesis of Amine/Aniline Compounds of Formula (I)

Preparation of5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)thiazol-2-amine(Compound I-18).

Step 1: Preparation of 1-(2,6-difluorophenyl)cyclopropan-1-amine.

To an oven-dried 200 mL round-bottom flask containing a 1,5-inchegg-shaped stirbar under N₂ atmosphere was added2,6-difluorobenzonitrile (2.78 g, 20 mmol), followed by methyltert-butyl ether (MTBE) (100 mL). The pale yellow solution was cooled to−78° C. and titanium tetraisopropoxide (7.3 mL, 24 mmol, 1.2 equiv.) wasin one portion. Ethylmagnesium bromide (3M in ether, 16.7 mL, 50 mmol,2.5 equiv.) was added dropwise over the course of 5 minutes withvigorous stirring, yielding a pale yellow homogeneous solution (caution:potential for exotherm and gas evolution). No gas evolution was observedin this case. The dry ice bath was left to expire slowly over the courseof 4 hours with vigorous stirring (1500 RPM) of the solution. Uponwarming to room temperature, a viscous opaque brown solution is formed.This solution was cooled to 0° C. in an ice bath. Then, BF₃.OEt₂ (4.9mL, 40 mmol, 2 equiv.) was added dropwise over the course of 5 minutes(caution: exothermic, gas evolution). The ice bath was removed and theopaque brown suspension was allowed to warm to room temperatureovernight. The following day, the reaction was quenched by adding 1MNaOH (100 mL, 5 equiv.) in small portions at first, followed by EtOAc(50 mL), and then stirred vigorously at room temperature for 2 hours toyield a biphasic mixture of a top colorless organic layer and a bottomdark blue aqueous emulsion. This biphasic mixture was filtered directlythrough water-wetted celite, washed once with water (50 mL) and oncewith EtOAc (50 mL). The filtrate was collected and the layers separated.The aqueous layer was extracted twice more with EtOAc (50 mL). Thecombined organic layers were washed twice with water (50 mL) and oncewith brine (25 mL), then dried over MgSO₄, filtered and concentrated byrotary evaporation. The crude product was purified by columnchromatography (Silica gel, 0-50% EtOAc in hexanes) to afford the titlecompound.

Step 2.: Preparation of methyl2-((1-(2,6-difluorophenyl)cyclopropyl)amino)-thiazole-5-carboxylate.

To a tail scintillation vial with a silicone cap under N₂ atmosphere(balloon) was added 1-(2,6-difluorophenyl)cyclopropan-1-amine (169 mg,1.0 mmol, 1 equiv), methyl 2-chlorothiazole-5-carboxylate (195 mg, 1.1mmol, 1.1 equiv), DIPEA (0.87 mL, 5 mmol, 5 equiv), and DMSO (3 mL). Theorange biphasic clear mixture was heated to 110° C. overnight (12hours), and it became a monophasic brown solution. The following day,LCMS and TLC analysis indicated complete conversion of thecyclopropylamine to a complex mixture of products. The reaction wasallowed to cool to room temperature, then poured into water (50 mL) andextracted with EtOAc (3×50 mL). The combined organics were washed withwater, then brine, then dried over MgSO₄, filtered and concentrated byrotary evaporation. The crude product, a dark brown oil, was dry loadedonto silica gel and purified by flash column chromatography (0-50% EtOAcin hexanes gradient) to provide the title compound as a brown oil, 47.9mg (15% yield).

Step 3: Preparation of2-((1-(2,6-difluorophenyl)cyclopropyl)amino)thiazole-5-carbohydrazide.

To a tall scintillation vial with a red PTFE cap under N₂ atmosphere(balloon) was added methyl2-((1-(2,6-difluorophenyl)cyclopropyl)amino)thiazole-5-carboxylate (30.0mg, 0.97 mmol, 1 equiv.), 1,4-dioxane (1 mL), and lastly hydrazinemonohydrate (0.05 mL, 1 mmol, 10 equiv.). The homogeneous orangesolution was heated to 100° C. for 64 h, after which time LCMS analysisindicated complete conversion to the desired acyl hydrazide. The mixturewas cooled to room temperature, then poured into water (50 mL) andextracted three times with EtOAc (50 mL). The combined organics werewashed with water, then brine, then dried over MgSO₄, filtered andconcentrated by rotary evaporation to provide the title compound as abrown oil of sufficient purity to take forward directly to the nextstep, 25.1 mg (84% yield).

Step 4: Preparation ofN-(2,2-difluoroacetyl)-2-((1-(2,6-difluorophenyl)-cyclopropyl)amino)thiazole-5-carbohydrazide.

To a vial was added2-((1-(2,6-difluoropheny)cyclopropyl)amino)thiazole-5-carbohydrazide(25.1 mg, 0.081 mmol, 1 equiv.) and DCM (1 mL). The heterogeneous orangesuspension was cooled to 0° C. in an ice bath. Lastly, difluoroaceticanhydride (DFAA, 0.02 mL, 0.16 mmol, 2 equiv.) was added dropwise over30 seconds. The resulting homogeneous orange solution was allowed towarm to room temperature. After 30 minutes, LCMS analysis indicatedcomplete conversion to the desired diacyl hydrazide. The reaction wasquenched by the addition of 1 mL saturated aqueous NaHCO₃ and 1 mLmethanol, and was stirred at room temperature for 1 hour. Then, thereaction mixture was poured into 50 mL half-saturated NaHCO₃ andextracted three times with EtOAc (50 mL). The combined organics werewashed with water, then brine, then dried over MgSO₄, filtered andconcentrated by rotary evaporation to provide the title compound as awaxy orange solid, 22.9 mg (73% yield).

Step 5: Preparation of5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)thiazol-2-amine.

To a 0.5-2 mL microwave vial was added a stifling flea,N′-(2,2-difluoroacetyl)-2-((1-(2,6-difluorophenyl)cyclopropyl)amino)thiazole-5-carbohydrazide(22.9 mg, 0.06 mmol, 1 equiv) as a solution in THF (1 mL), and lastlyBurgess reagent (70.6 mg, 0.3 mmol, 5 equiv). The mixture waspre-stirred for 2 minutes, then heated to 150° C. in a microwave for 2hours at approximately 8 bar of pressure. After the reaction, thereaction was an orange natant with a sinking brown oil. LCMS analysis ofthe orange natant indicated complete conversion of the diacyl hydrazideto the desired oxadiazole. The reaction mixture was poured into water(50 mL) and extracted three times with EtOAc (50 mL). The combinedorganics were washed with water, then brine, then dried over MgSO₄,filtered and concentrated by rotary evaporation to provide the crudematerial as a yellow oil. The crude material was dry loaded onto silicagel and purified by flash column chromatography (0-50% EtOAc in hexanesgradient) to provide the title compound as a pale yellow solid, 16.6 mg,of still insufficient purity. The material was subjected to preparativeHPLC purification (10-100% MeCN in water with 0.1% TFA), theproduct-containing fractions were frozen at −78° C. and lyophilized toprovide the purified title compound as a fluffy white solid, 4.1 mg (19%yield).

Preparation of5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-phenethylthiazol-2-amine(Compound I-19).

Step 1: Preparation of methyl 2-(phenethylamino)thiazole-5-carboxylate.

To a tall scintillation vial with a PTFE cap under N₂ atmosphere(balloon) was added methyl 2-bromothiazole-5-carboxylate (444 mg, 2.0mmol, 1 equiv.), 2-phenethylamine (0.30 mL, 2.4 mmol, 1.2 equiv.), DMSO(6 mL) and DIPEA (1.7 mL, 10 mmol, 5 equiv.). The pale yellow-orangebiphasic clear mixture was heated to 110° C. for 2 hours, after whichLCMS analysis indicated clean complete conversion to the desiredproduct. The reaction was cooled to room temperature, then poured intohalf-saturated aqueous NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL).The combined organics were washed with water, then brine, then driedover MgSO₄, filtered and concentrated by rotary evaporation to provide acrude red solid, which was dry loaded onto silica gel and purified byflash column chromatography (0-50% EtOAc in hexanes gradient) to providethe title compound as a light pink solid, 395.5 mg (75% yield).

Step 2: Preparation of 2-(phenethylamino)thiazole-5-carbohydrazide.

To a tall scintillation vial with a PTFE cap under N₂ atmosphere(balloon) was added methyl 2-(phenethylamino)thiazole-5-carboxylate (131mg, 0.5 mmol, 1 equiv), followed by 1,4-dioxane (2 mL), and lastlyhydrazine hydrate (0.24 mL, 5 mmol, 10 equiv). The light yellow biphasicclear mixture was heated to 100° C. overnight, after which LCMS analysisindicated complete conversion to the desired acyl hydrazide. Thereaction was poured into water (50 mL), then extracted 3 times withEtOAc (50 mL). The combined organic layers were washed with water, thenbrine, then dried over MgSO₄, filtered and concentrated by rotaryevaporation to provide the crude product as a light orange solid insufficient purity to take forward directly, 105.1 mg (80% yield).

Step 3: Preparation ofN′-(2,2-difluoroacetyl)-2-(phenethylamino)thiazole-5-carbohydrazide.

To a scintillation vial was added2-(phenethylamino)thiazole-5-carbohydrazide (52.5 mg, 0.2 mmol),followed by DCM (1 mL). The heterogeneous white suspension was cooled to0° C. in an ice bath. Then, difluoroacetic anhydride (DFAA, 0.05 mL, 0.4mmol, 2 equiv) was added dropwise over 30 seconds. The now fullyhomogeneous pale yellow solution was allowed to warm to room temperaturefor 30 minutes, after which LCMS analysis indicated complete conversionto a mixture of the desired product and a side product in which theaminothiazole NH was also acylated, favoring the latter. The acylatedaminothiazole was chemoselectively deprotected in situ by adding 1 mLmethanol, followed by 1 mL saturated aqueous Na₂CO₃, and stirring theheterogeneous biphasic mixture at room temperature for 1 hour. Then, themixture was poured into 50 mL water (50 mL), then extracted 3 times withEtOAc (50 mL). The combined organic layers were washed with water, thenbrine, then dried over MgSO₄, filtered and concentrated by rotaryevaporation to provide the crude product as a pale yellow-orange solidin sufficient purity to take forward directly to the next step, 23.2 mg(34%).

Step 4: Preparation of5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-phenethylthiazol-2-amine.

To a small microwave vial (0.5-2 mL) containing a magnetic stirring fleawas addedN′-(2,2-difluoroacetyl)-2-(phenethylamino)thiazole-5-carbohydrazide(23.2 mg, 0.068 mmol, 1 equiv) as a solution in THF (1 mL). Then,Burgess reagent (81.6 mg, 0.34 mmol, 5 equiv) was added, the vialcrimped and microwaved for 2 hours at 150° C. at approximately 8 bar.After cooling to room temperature, the reaction contains a sinking brownoil with a clear yellow natant. LCMS analysis of the yellow natantindicated complete conversion of the diacylhydrazide starting materialto the desired oxadiazole, along with multiple minor impurities. Then,the mixture was poured into 50 mL water (50 mL), then extracted 3 timeswith EtOAc (50 mL). The combined organic layers were washed with water,then brine, then dried over MgSO₄, filtered and concentrated by rotaryevaporation to provide a crude pale yellow oil. The material was dryloaded onto silica gel and purified by flash column chromatography(0-50% EtOAc/hexanes gradient) to provide the title compound as a waxywhite solid, 13.8 mg (63% yield).

Example 8. Preparation of2-(2-((3-chlorophenoxy)methyl)thiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole(Compound I-71)

To a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (30mg, 0.1 mmol) and 3-chlorophenol (16 mg, 0.12 mmol)) inN,N-dimethylformamide (1 mL) was added potassium carbonate (42 mg, 0.3mmol). The mixture was stirred at 20° C. for 1 hour and filtered. Thefiltrate was concentrated to dryness under reduced pressure. The residuewas purified by RP-HPLC (55-85% acetonitrile in water and 0.225% formicacid) to afford2-[2-[(3-chlorophenoxy)methyl]thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole(9.7 mg, 28%) as a yellow solid.

Example 9. Synthesis of Regioisomeric Thiazole/Oxazole Compounds ofFormula (I)—Amides

Preparation ofN-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanecarboxamide(Compound I-84).

N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanecarboxamide

Step 1: 2-methylthiazole-4-carbohydrazide

To a solution of ethyl 2-methylthiazole-4-carboxylate (5.0 g, 29.2 mmol)in ethanol (50 mL) was added hydrazine hydrate (16.5 g, 280.4 mmol) at20° C. Then the reaction was stirred at 90° C. for 16 hours andconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0-10% methanol indichloromethane) to afford 2-methylthiazole-4-carbohydrazide (2.2 g,48%) as a yellow solid. LCMS R_(T)=0.483 min, m/z=158.2 [M+H]⁺.

Step 2: N-(2,2-difluoroacetyl)-2-methyl-thiazole-4-carbohydrazide

To a solution of 2-methtylthiazole-4-carbohydrazide (2.0 g, 12.7 mmol)and N,N-Diisopropylethylamine (1.6 g, 12.7 mmol) in tetrahydrofuran (20mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (2.7g, 15.3mmol). The reaction was stirred at 20° C. for 16 hours and concentratedto dryness under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-5% methanol indichloromethane) to affordN′-(2,2-difluoroacetyl)-2-methyl-thiazole-4-carbohydrazide (2.8 g, 94%)as a white solid.

Step 3: 2-(difluoromethyl)-5-(2-methylthiazol-4-y)-1,3,4-oxadiazole

To a solution ofN′-(2,2-difluoroacetyl)-2-methyl-thiazole-4-carbohydrazide (2.8 g, 11.9mmol) in tetrahydrofuran (30 mL) was added Burgess reagent (7.1 g, 29.8mmol). The mixture was stirred at 90° C. under microwave for 3 hours.The mixture was cooled and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by column chromatography(silica gel, 100-200 mesh, 0-25% ethyl acetate in petroleum ether) toafford 2-(difluoromethyl)-5-(2-methylthiazol-4-yl)-1,3,4-oxadiazole (1.4g, 54%) as a white solid.

Step 4:2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole

To a solution of2-(difluoromethyl)-5-(2-methylthiazol-4-yl)-1,3,4-oxadiazole (150 mg,0.69 mmol) in carbon tetrachloride (5 mL) were added N-bromosuccinimide(135 mg, 0.76 mmol) and azodiisobutyronitrile (11 mg, 0.07 mmol). Themixture was stirred at 80° C. for 16 hours and filtered. The filtratewas concentrated under reduced pressure. The residue was purified byRP-TLC (petrleum ether:ethyl acetate=3:1) to afford2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (70mg, 34%) as colorless oil. LCMS R_(T)=1.048 min, m/z=297.7 [M+H]⁺.

Step 5: N-(3-chlorophenyl)cyclopropanecarboxamide

To a mixture of 3-chloroaniline (1.0 g, 7.84 mmol) and triethylamine(1.6 g, 15.68 mmol) in tetrahydrofuran (16 mL) was addedcyclopropanecarbonyl chloride (901 mg, 8.62 mmol) at 0° C. After stirredat 20° C. for 16 hours, the reaction was quenched by addition of water(100 mL) and extracted with ethyl acetate (60 mL×3). The combinedorganic layers were dried over sodium sulphate and concentrated todryness under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-25% ethyl acetate inpetroleum ether) to afford N-(3-chlorophenyl)cyclopropanecarboxamide(1.45 g, 95% yield) as a white solid.

Step 6:N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanecarboxamide(I-84)

To a solution of N-(3-chlorophenyl)cyclopropanecarboxamide (66 mg, 0.34mmol) in tetrahydrofuran (3 mL) was added sodium hydride (12 mg, 0.30mmol, 60% purity) at 0° C. under nitrogen atmosphere. After stirred for30 mins at 0° C., the reaction mixture was added2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50mg, 0.17 mmol) and stirred at 25° C. for 30 mins. The reaction wasquenched by addition of water (50 mL) and extracted with ethyl acetate(50 mL×3). The combined organic layers were dried over sodium sulphateand concentrated to dryness under reduced pressure. The residue waspurified by RP-HPLC (53 to 83% acetonitrile in water and 0.225% formicacid) to affordN-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]cyclopropanecarboxamide(11.3 mg, 16%) as a white solid.

The methods used in Example 9 were also used to prepare compound I-82.

Example 10. Synthesis of Regioisomeric Thiazole/Oxazole Compounds ofFormula (I)—Sulfonamides

Preparation ofN-(3-chlorophenyl)-N-((4-(5-(diflooromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide(Compound I-83)

Step 1: N-(3-chlorophenyl)cyclopropanesulfonamide

To a mixture of cyclopropanesulfonyl chloride (1.33 g, 9.43 mmol) andpyridine (930 mg, 11.76 mmol) in dichloromethane (10 mL) was added3-chloroaniline (1.00 g, 7.84 mmol) at 0° C. After stirred at 20° C. for16 hours, the reaction was quenched by addition of water (70 mL) andextracted with ethyl acetate (60 mL×3). The combined organic layers weredried over sodium sulphate and concentrated to dryness under reducedpressure. The residue was purified by column chromatography (silica gel,100-200 mesh, 0-20% ethyl acetate in petroleum ether) to affordN-(3-chlorophenyl)cyclopropanesulfonamide (1.70 g, 94% yield) as ayellow solid.

Step 2:N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide(Compound I-83)

A mixture of2-[2-(bromomethyl)thiazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole(35.0 mg, 0.12 mmol), N-(3-chlorophenyl)cyclopropanesulfonamide (33.0mg, 0.14 mmol) and potassium carbonate (49 mg, 0.35 mmol) inN,N-dimethylformamide (1 mL) was stirred at 30° C. for 1 hour andconcentrated under reduced pressure. The residue was purified by RP-HPLC(45 to 75% acetonitrile in water and 0.225% formic acid) to affordN-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]cyclopropanesulfonamide(25.2 mg, 47.2% yield) as a white solid.

Preparation ofN-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)oxazol-2-yl)methyl)cyclopropanesulfonamide(Compound I-86).

Step 1: 2-methyloxazole-4-carbohydrazide

To a solution of ethyl 2-methyloxazole-4-carboxylate (4.5 g, 29.00 mmol)in ethyl alcohol (80 mL) was added hydrazine hydrate (15.8 g, 316.62mmol). After stirred at 90° C. for 16 hours, the mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-10% methanol indichloromethane) to afford 2-methyloxazole-4-carbohydrazide (3.5 g, 86%)as an orange solid.

Step 2: N-(2,2-difluoroacetyl)-2-methyl-oxazole-4-carbohydrazide

To a solution of 2-methyloxazole-4-carbohydrazide (3.5 g, 24.94 mmol)and N-ethyl-N-isopropylpropan-2-amine (3.87 g, 29.93 mmol) intetrahydrofuran (38 mL) was added (2,2-difluoroacetyl)2,2-difluoroacetate (5.21 g, 29.93 mmol). After stirred at 20° C. for 3hours, the mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (silica gel, 100-200 mesh, 0-10%methanol in dichloromethane) to affordN′-(2,2-difluoroacetyl)-2-methyl-oxazole-4-carbohydrazide (5.0 g, 91%)as a yellow solid.

Step 3 : 2-(difluoromethyl)-5-(2-methyloxazol-4-yl)-1,3,4-oxadiazole

To a solution ofN-(2,2-difluoroacetyl)-2-methyl-oxazole-4-carbohydrazide (3.0 g, 13.69mmol) in tetrahydrofuran (8 mL) was added Burgess reagent (8.16 g, 34.22mmol). The mixture was stirred at 90° C. for 3 hours under microwave andthen quenched by addition of water (30 mL). The mixture was extractedwith ethyl acetate (50 mL×3). The organic extracts were dried oversodium sulphate and concentrated to dryness under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-80% ethyl acetate in petroleum ether) to afford2-(difluoromethyl)-5-(2-methyloxazol-4-yl)-1,3,4-oxadiazole (1.14 g,41%) as a yellow solid.

Step 4:2-[2-(bromomethyl)oxazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole

To a solution of2-(difluoromethyl)-5-(2-methyloxazol-4-yl)-1,3,4-oxadiazole (1.14 g,5.65 mmol) in tetrachloromethane (20 mL) was added2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile (93 mg, 0.56 mmol)and N-bromosuccinimide (2.52 g, 14.13 mmol). After stirred at 90° C. for16 hours, the reaction mixture was concentrated under reduced pressure.The residue was purified by RP-TLC (petroleum ether:ethyl acetate=2:1)to afford2-[2-(bromomethyl)oxazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (200mg, 10%) as a white solid. LCMS R_(T)=1.222 min, m/z=279.8 [M+H]⁺.

Step 5:N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)oxazol-2-yl)methyl)cyclopropanesulfonamide(Compound I-86)

A mixture of2-[2-(bromomethyl)oxazol-4-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (30mg, 0.11 mmol), N-(3-chlorophenyl)cyclopropanesulfonamide (25 mg, 0.11mmol) and potassium carbonate (30 mg, 0.22 mmol) inN,N-dimethylformamide (1 mL) was stirred at 20° C. for 1 hour andfiltered.. The filtrate was concentrated under reduced pressure. Theresidue was purified by RP-HPLC (40-70% acetonitrile in water and 0.04%ammonium hydroxide and 10 mM ammonium bicarbonate) to affordN-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]oxazol-2-yl]methyl]cyclopropanesulfonamide(17.2 mg, 37%) as a white solid.

The method described in Example 10 was also used to prepare compoundI-85.

Example 11. Preparation ofN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-sulfonamide(I-144)

Step 1:N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1,5-dimethyl-pyrazol-4-amine

To a solution of2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (30mg, 0.1 mmol) in N,N-dimethylformamide (0.5 mL) was added sodiumbicarbonate (26 mg, 0.3 mmol) and 1,5-dimethylpyrazol-4-amine (14 mg,0.12 mmol). After stirring at 20° C. for 16 h, the mixture wasconcentrated to dryness under reduced pressure. The residue was purifiedby preparative TLC (petroleum ether:ethyl acetate=1:1) to affordN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1,5-dimethyl-pyrazol-4-amine(30 mg, 74%) as a yellow oil.

Step 2:N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-sulfonamide

To a solution ofN-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1,5-dimethyl-pyrazol-4-amine(27 mg, 0.08 mmol) in dichloromethane (0.5 mL) was added pyridine (20mg, 0.25 umol) and ethanesulfonyl chloride (13 mg, 0.1 mmol). Afterstirring at 20° C. for 16 h, the mixture was concentrated to drynessunder reduced pressure. The residue was purified by RP-HPLC (0 to 40%acetonitrile in water and 0.2% formic acid) to affordN-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-sulfonamide(13 mg, 36%) as a white solid.

Example 12. Preparation of3-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (CompoundI-11)

Step 1: preparation of methyl 2-methylthiazole-5-carboxylate.

To a 1 L round bottom flask was added 2-methyl-1,3-thiazole-5-carboxylicacid (10.0 g, 70 mmol) and MeOH (100 mL). The reaction mixture was thencooled to 0° C., and thionyl chloride (13 mL, 180 mmol) was added in adropwise fashion. The reaction mixture was stirred at reflux for 16 h.The reaction mixture was partially concentrated then diluted with EtOAc.The organic layer was washed with water, brine, dried over MgSO₄, thenconcentrated to afford the title compound as a white solid, which wasused without further purification (11.0 g, 100%).

Step 2: 2-methylthiazole-5-carboxamide.

To a 250 mL round bottom flask was added methyl2-methyl-1,3-thiazole-5-carboxylate (11.0 g, 70 mmol) and an aqueoussolution of ammonium hydroxide (28% NH₃ in H₂O, 140 mL). The reactionmixture was stirred for 3 h during which a white precipitate formed. Thecrude reaction mixture was diluted with water, and the product wasextracted with EtOAc (15×). The combined organic layers were dried overMgSO₄, then concentrated to afford the title compound as a white solid(8.11 g, 81%).

Step 3: 2-methylthiazole-5-carbonitrile.

To a 100 mL round bottom flask was added2-methyl-1,3-thiazole-5-carboxamide (4.00 g, 28.1 mmol), tosyl chloride(13.4 mg, 70.3 mmol), and pyridine (20 mL). The reaction mixture wasstirred at 50° C. for 3 h. The reaction mixture was diluted with EtOAc,washed with ˜1 M HCl (aq), water, sat. NaHCO₃ (aq), then brine. Theorganic layer was dried over MgSO₄, then concentrated to afford thetitle compound as a brown solid (2.30 g, 66%).

Step 4: N′-hydroxy-2-methylthiazole-5-carboximidamide.

To a 500 mL round bottom flask was added2-methyl-1,3-thiazole-5-carbonitrile (2.30 g, 18.5 mmol),8-hydroxyquinoline (13.4 mg, 0.093 mmol), and ethanol (180 mL). To thereaction mixture was added a solution of hydroxylamine hydrochloride(5.15 g, 74.1 mmol) in water (26 mL) and a solution of sodium carbonate(6.4 g, 59.3 mmol) in water (53 mL) in a sequential manner. The reactionmixture was then stirred at 78° C. for 16 h. The reaction mixture wasthen concentrated to remove ethanol, diluted with water, then acidifiedto pH 5 with 2M HCl (aq). The product was extracted with EtOAc (6×),dried over MgSO₄, then concentrated to afford the title compound as abrown solid (2.91 g, 89%).

Step 5: 3-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole.

To a 20 mL vial was added(Z)-N′-hydroxy-2-methylthiazole-5-carboximidamide (247 mg, 0.54 mmol)and pyridine (3.8 mL). The reaction mixture was cooled to 0° C., andTFAA (0.66 mL, 4.7 mmol) was added in a dropwise fashion. The reactionmixture was stirred at 0° C. for 15 min, then stirred warming to ambienttemperature for 45 min. The crude reaction mixture was diluted withEtOAc, then washed with 1 M HCl (aq), water, then brine. The organiclayer was then dried over MgSO₄ and concentrated. The resulting residuewas adsorbed onto celite then purified by column chromatography (0-15%EtOAc/hexanes) to afford the title compound as a yellow oil (369 mg,58%). ¹H NMR (400 MHz, chloroform-d) δ ppm 8.38 (s, 1H) 2.82 (s, 3H).LCMS: tR (min): 4.90 (20-100% ACN with 0.1% TFA 6 min.); m/z [M+H]⁺requires: 236.0; found: 236.0. HPLC tR (min) 6.34, 99% (10-100% ACN with0.1% TFA 10 min).

Example 13. Preparation ofN-(3-chlorophenyl)-N-((5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide(Compound I-12)

Step 1:3-(2-(bromomethyl)thiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole.

To a 20 mL vial was added3-(2-methylthiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxa.diazole (208 mg,0.88 mmol), NBS (283 mg, 1.59 mmol), AIBN (7.3 mg, 0.044 mmol), and DCE(9.0 mL). The reaction mixture was stirred at 84° C. for 16 h. The crudereaction mixture was diluted with EtOAc, washed with water, washed withbrine, dried over MgSO₄, then concentrated. To the resulting residue wasadded THF (9.0 mL). The reaction mixture was cooled to 0° C., then DIPEA(0.13 mL, 0.88 mmol) and diethyl phosphite (0.09 mL, 0.9 mmol) wereadded sequentially in a dropwise fashion. The reaction mixture wasstirred warming to ambient temperature for 2 h. The reaction mixture wasconcentrated then diluted with EtOAc, washed with water, washed withbrine, dried over MgSO₄, then concentrated. The crude product wasadsorbed onto celite then purified by column chromatography (0-10%EtOAc/hexanes) to afford the title compound as a white solid (174 mg,62%).

StepN-(3-chlorophenyl)-N-((5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide.

To a 2 dram vial was added 60 wt % NaH in mineral oil (8.3 mg, 0.21mmol) and DMF (0.5 mL). The reaction mixture was cooled to 0° C., then asolution of N-(3-chlorophenyl)cyclopropanesulfonamide (40.6 mg, 0.18mmol) in DMF (0.5 mL) was added in a dropwise fashion. The reactionmixture was stirred warming to ambient temperature for 20 min. Thereaction mixture was then cooled to 0° C., then a solution of3-(2-(bromornethyl)thiazol-5-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole(50.0 mg, 0.16 mmol) in DMF (1.0 mL) was added in a dropwise fashion.After 4 h, the reaction mixture was quenched with water and diluted withbrine. The product was extracted with EtOAc (3×). The combined organiclayers were washed with water (4×), washed with brine, dried over MgSO₄,then concentrated. The resulting residue was adsorbed onto celite andpurified by column chromatography (0-70% EtOAc/hexanes) to yield thetitle compound as an orange solid (16.6 mg, 22%).

Example 14. Preparation ofN-[[2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-5-yl]methyl]-N-(5-fluoro-3-pyridyl)ethanesulfonamide(I-264)

Step 1: tert-butyl N-[(5-methylthiazole-2-carbonyl)amino]carbamate

To a mixture of 5-methylthiazole-2-carboxylic acid (3.0 g, 20.95 mmol)in dichloromethane (50 mL) was addedN-(3-dimethylaminopropyl)-n-ethylcarbodiimidehydrochloride (4.8 g, 25.15mmol) and 1-hydroxybenzotriazole (1.42 g, 10.48 mmol). After stirring at20° C. for 15 min, the reaction was added tert-butyl N-aminocarbamate(3.3 g, 25.15 mmol). After stirring at 20° C. for 16 hours, the reactionwas quenched by addition of water (100 mL) and extracted withdichloromethane (2×100 mL). The combined organic extracts were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel, 100-200mesh, 0-20% ethyl acetate in petroleum ether) to afford tert-butylN-[(5-methylthiazole-2-carbonyl)amino]carbamate (4.16 g, 75%) as acolorless oil.

Step 2: 5-methylthiazole-2-carbohydrazide

A solution of tert-butyl N-[(5-methylthiazole-2-carbonyl)amino]carbamate(4.07 g, 15.82 mmol) in hydrochloric acid (4.0 M in ethyl acetate, 40.0mL, 160.00 mmol) was stirring at 20° C. for 2 hours and filtered. Thecollected solid was dried under reduced pressure to afford5-methylthiazole-2-carbohydrazide hydrochloride (3.2 g, crude) as awhite solid.

Step 3: N′-(2,2-difluoroacetyl)-5-methyl-thiazole-2-carbohydrazide

A solution of 5-methylthiazole-2-carbohydrazide hydrochloride (3.0 g,crude) in tetrahydrofuran (30 mL) was addedN-ethyl-N-isopropylpropan-2-amine (4.0 g, 30.98 mmol) and(2,2-difluoroacetyl) 2,2-difluoroacetate (3.2 g, 18.59 mmol) at 0° C.After stirring at 20° C. for 1 hour, the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-5% methanol indichloromethane) to affordN′-(2,2-difluoroacetyl)-5-methyl-thiazole-2-carbohydrazide (2.0 g, 54%)as a white solid.

Step 4: 2-(difluoromethyl)-5-(5-methylthiazol-2-yl)-1,3,4-oxadiazole

A mixture of N′-(2,2-difluoroacetyl)-5-methyl-thiazole-2-carbohydrazide(1.0 g, 4.25 mmol) and Burgess reagent (3.0 g, 12.75 mmol) intetrahydrofuran (15 mL) was heated under microwave at 90° C. for 3hours. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-15% ethyl acetate in petroleum ether)) to afford2-(difluoromethyl)-5-(5-methylthiazol-2-yl)-1,3,4-oxadiazole (712 mg,32%) as a white solid.

Step 5: 2-[5-(bromomethyl)thiazol-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole

To a solution of2-(difluoromethyl)-5-(5-methylthiazol-2-yl)-1,3,4-oxadiazole (610 mg,2.81 mmol) in 1,2-dichloroethane (20 mL) was added N-bromosuccinimide(550 mg, 3.09 mmol) and azodiisobutyronitrile;azobisisobutyronitrile (23mg, 0.14 mmol). After stirring at 80° C. for 3 hours, the reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0-20% ethylacetate in petroleum ether) to afford2-[5-(bromomethyl)thiazol-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (743mg, 73%) as a white solid.

Step 6:N-[[2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-5-yl]methyl]-N-(5-fluoro-3-pyridyl)ethanesulfonamide

To a solution of2-[5-(bromomethyl)thiazol-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50mg, 0.7 mmol) in N,N-dimethylformamide (1 mL) was added sodiumbicarbonate (43 mg, 0.51 mol) andN-(5-fluoro-3-pyridyl)ethanesulfonamide (41 mg, 0.2 mmol). Afterstirring at 20° C. for 1 hour, the mixture was filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by RP-HPLC (35 to 65% acetonitrile in water and 0.225% formicacid) to affordN-[[2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-5-yl]methyl]-N-(5-fluoro-3-pyridyl)ethanesulfonamide(37 mg, 51%) as colorless oil.

The methods described in Example 14 were also used to prepare thefollowing compounds: I-257, I-259, I-260, I-261, I-262, and I-263.

Example 15. Preparation of3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-2-ol(I-258)

To a solution of 1,3-dihydropyrrolo[2,3-c]pyridin-2-one (25 mg, 0.19mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (60%, 7mg, 0.17 mmol). After stirring at 0° C. for 0.5 hour, the reaction wasadded2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (50mg, 0.17 mmol). After stirring at 20° C. for another 0.5 hour, themixture was filtered. The filtrate was concentrated under reducedpressure. The residue was purified by RP-HPLC (10 to 40% acetonitrile inwater and 0.225% formic acid) to afford3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1H-pyrrolo[2,3-c]pyridin-2-ol(10.3 mg, 17%) as a red solid.

Example 16. Synthesis of N-Alkyl Amide Pyridinone Compounds of Formula(I)

Preparation of4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (II-12),tert-butyl2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetate(Compound II-11),2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)aceticacid (Compound II-10) and4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-morpholino-2-oxoethyl)pyridin-2(1H)-one(Compound II-1)

Step 1: Preparation of 4-(2H-tetrazol-5-yl)pyridin-2(1H)-one, HCl salt.

To a 100 mL round-bottom flask containing a 1-inch egg-shaped stirbar,fitted with an air condensor and under N₂ atmosphere (balloon), wasadded 2-oxo-1,2-dihydropyridine-4-carbonitrile (1.00 g, 8.33 mmol, 1equiv), followed by sodium azide (1.62 g, 25.0 mmol, 3 equiv), ammoniumchloride (1.34 g, 25.0 mmol, 3 equiv) and lithium chloride (529 mg, 12.5mmol, 1.5 equiv). Lastly, DMF (20 mL) was added, and the pinkheterogeneous suspension was vigorously stirred at 110° C. for 16 hours,after which LCMS analysis indicated clean, complete conversion to thedesired tetrazole product. The reaction mixture was allowed to cool toroom temperature, then 50 mL of water was added to form a pale orangehomogeneous solution (pH=6). Concentrated aqueous HCl (approximately 2mL) was added dropwise over 2 minutes with vigorous stirring until pH=1.Upon acidification, the desired tetrazole HCl salt precipitated out as alight beige solid. The suspension was filtered, and the light beigesolid was washed with water (20 mL), followed by hexanes (20 mL), andthen left to air-dry on the filter for 10 minutes. (Caution: thefiltrate contains hydrazoic acid, which is volatile, toxic andexplosive. Acidic aqueous solutions of hydrazoic acid can be safelyquenched by the addition of sodium nitrite until spotting onstarch-iodide paper gives a dark blue spot, indicating completedecomposition of hydrazoic acid). The wet solid obtained was dried onvacuum overnight to remove residual water to afford the title compoundHCl salt as a free-flowing beige solid, 1.21 g (73%).

Step 2: Preparation of4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (CompoundII-12).

To a 100 mL round-bottom flask containing a 1-inch egg-shaped stirbar,fitted with an air condensor and under N₂ atmosphere (balloon), wasadded 4-(2H-tetrazol-5-yl)pyridin-2(1H)-one (HCl salt, 600 mg, 3.01mmol, 1 equiv), followed by 1,4-dioxane (20 mL), and potassium carbonate(1.69 g, 12.0 mmol, 4 equiv). The beige heterogeneous suspension wasstirred vigorously at room temperature for 5 minutes, after which timedifluoroacetic anhydride (DFAA, 0.70 mL, 6.0 mmol, 2 equiv) was addeddropwise over 2 minutes, with no immediate visible changes to thereaction. The reaction is heated to 90° C. overnight (16 hours) withvigorous stirring, after which LCMS analysis indicated approximately 80%clean conversion to the desired oxadiazole. Deemed sufficient, thereaction was allowed to cool to room temperature, then poured into 30 mLwater, resulting in a dark yellow-orange homogeneous solution (pH=10).The basic aqueous layer was extracted three times with EtOAc (50 mLeach), the organic layers washed with minimal saturated aqueous NaHCO₃(10 mL), then brine (10 mL), then dried over MgSO₄, filtered andconcentrated by rotary evaporation. The resulting yellow solid was takenup in MTBE (10 mL) and sonicated to make a fine suspension, thenfiltered to afford the title compound as a white solid, 477 mg (74%yield).

The method used to prepare compound II-12 was also used to prepareCompound II-6.

Step 3: Preparation of tert-butyl2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetate(Compound II-11).

To a scintillation vial containing a magnetic stirring flea was added4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (140 mg,0.66 mmol, 1 equiv) and DMF (2 mL). The homogeneous orange solution wascooled to 0° C. in an ice bath. Potassium carbonate (461 mg, 3.3 mmol, 5equiv) was added. Lastly, tert-butyl bromoacetate (0.29 mL, 2.0 mmol, 3equiv) was added all at once. After 1 hour, LCMS analysis of the fineorange suspension indicated complete conversion to a >10:1 mixture ofthe N-alkylated to the O-alkylated pyridone. The N-alkylated pyridone ismuch more polar by both LCMS and TLC than the O-alkylated pyridone.Also, the N-alkylated pyridone exhibits bright blue fluorescence on TLCwith 254 nm excitation. The reaction was worked up by pouring into 50 mLwater, then extracting from the aqueous layer three times with EtOAc (50mL). The combined organic layers were washed with water, then brine,then dried over MgSO₄, filtered and concentrated by rotary evaporation.The crude pale yellow oil was dry-loaded onto silica gel and purified byflash column chromatography (0-50% EtOAc in hexanes gradient) to providethe title compound as a white solid, 188.0 mg (87% yield). Connectivitywas assigned by NOESY (NOE cross-peak is observed between the alpha CH₂at 4.61 ppm and the most downfield pyridone doublet at 7.40 ppm).

The method used to prepare compound II-11 was also used to prepareCompound II-7.

Step 4: Preparation of2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)aceticacid (Compound II-10).

To a scintillation vial containing a magnetic stirring flea was addedtert-butyl2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetate(188 mg, 0.57 mmol, 1 equiv), followed by DCM (2 mL) and lastlytrifluoroacetic acid (TFA, 0.5 mL) dropwise over 1 minute at roomtemperature with stirring. The pale yellow homogeneous solution wasstirred at room temperature for 6 hours open to air, after which LCMSanalysis indicated about 96% clean conversion of the tert-butyl ester tothe free carboxylic acid. Deemed sufficient, the reaction mixture wasconcentrated directly by rotary evaporation to provide the crudematerial as a colorless viscous oil containing residual TFA. Thematerial was dissolved in 3 mL 1:1 acetonitrile:water, then frozen in adry-ice acetone bath at −78° C., then lyophilized overnight to providethe title compound as a pale yellow brittle solid of sufficient purity,165 mg (103% yield).

Step 5: Preparation of4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-morpholino-2-oxoethyl)pyridin-2(1H)-one.

To a scintillation vial was added2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)aceticacid (II-10, 27.1 mg, 0.10 mmol, 1 equiv.), followed by EtOAc (1 mL) andHATU (76.0 mg, 0.20 mmol, 2 equiv.). The heterogeneous white suspensionwas stirred at room temperature for 5 minutes, after which timemorpholine (0.025 mL, 0.30 mmol, 3 equiv.) followed by triethylamine(0.07 mL, 0.5 mmol, 5 equiv.) were each added dropwise with vigorousstirring at room temperature. The heterogeneous white suspension wasstirred at room temperature for 1 hour, after which LCMS analysisindicated complete conversion to the desired amide. The reaction waspoured into water (50 mL), then extracting from the aqueous layer threetimes with EtOAc (50 mL). The combined organic layers were washed withminimal water, then brine, then dried over MgSO₄, filtered andconcentrated by rotary evaporation to provide the crude product as ayellow oil. The material was dry loaded onto silica gel and purified byflash column chromatography (0-10% methanol in DCM gradient) to providethe title compound as a colorless oil, 7.8 mg (23% yield).

Any suitable amide coupling procedure known in the art can be used toprepare the disclosed compounds, including but not limited to:EDC/1-hydroxybenzotriazole (HOBT) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(EDAC)/HOBT/EtN(iPr₂)

The methods disclosed in Example 16 were also used to prepare thefollowing compounds: II-2 and II-18.

Example 17. Synthesis of N-Alkyl Pyridinone Compounds of Formula (I)Preparation of1-benzyl-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one(Compound II-4)

To a 1-dram vial containing a magnetic stirring flea was added4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (II-12,20.0 mg, 0.094 mmol, 1 equiv) and DMF (1 mL). The homogeneous orangesolution was cooled to 0° C. in an ice bath. Potassium carbonate (69 mg,0.5 mmol, 5 equiv) was added, followed by dropwise addition of benzylbromide (0.05 mL, 0.5 mmol, 5 equiv). The reaction was allowed to warmto room temperature. After 2 hours, LCMS analysis indicated completeconversion to a >10:1 mixture of N-alkylated to O-alkylated pyridones.The reaction was worked up by pouring into 50 mL water, then extractingfrom the aqueous layer three times with EtOAc (50 mL). The combinedorganic layers were washed with water, then brine, then dried overMgSO₄, filtered and concentrated by rotary evaporation. The crude paleyellow film was dry-loaded onto silica gel and purified by flash columnchromatography (0-50% EtOAc in hexanes gradient) to provide the titlecompound as a colorless oil which solidifies at room temperature into awaxy white solid, 25.3 mg (85% yield).

Preparation of4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-phenethylpyridin-2(1H)-one(Compound II-5)

To a 1-dram vial containing a magnetic stirring flea was added4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one (II-12,21.0 mg, 0.099 mmol, 1 equiv.) and DMF (1 mL). The homogeneous orangesolution was cooled to 0° C. in an ice bath. Potassium carbonate (69 mg,0.5 mmol, 5 equiv.) was added, followed by dropwise addition ofphenethyl bromide (0.07 mL, 0.5 mmol, 5 equiv.). The reaction wasallowed to warm to room temperature. After 2 hours, LCMS analysisindicated complete conversion to an approximately 2:1 ratio of N-linkedto O-linked pyridones (the selectivity is typically much greater for theN-linked pyridone than in this case). The reaction was worked up bypouring into 50 mL water, then extracting from the aqueous layer threetimes with EtOAc (50 mL). The combined organic layers were washed withwater, then brine, then dried over MgSO₄, filtered and concentrated byrotary evaporation. The crude pale yellow oil was dry-loaded onto silicagel and purified by flash column chromatography (0-50% EtOAc in hexanesgradient) to provide each of the two isomeric title compounds in highpurity (Connectivity was unambiguously verified by NOESY for bothisomers).

N-linked4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-phenethylpyridin-2(1H)-one.White solid, 18.3 mg (58% yield). LC-MS: tR (min) 4.39 (20-100% ACN with0.1%TFA 6 min), m/z [M+H]⁺ CH₁₆H₁₃F₂N₃O₂ requires: 317.1, found: 318.1.HPLC tR (min) 5.89, 97.9% (10-100% ACN with 0.1% TFA 10 min.)

O-linked2-(difluoromethyl)-5-(2-phenethoxypyridin-4-yl)-1,3,4-oxadiazole. Paleyellow oil which solidifies at room temperature into a waxy solid, 10.5mg (33% yield). ¹H NMR (400 MHz, chloroform-d) δ ppm 8.35 (br d, J=3.67Hz, 1H) 7.18 -7.59 (m, 7H) 6.73 -7.12 (m, 1H) 4.60 (br t, J=6.85 Hz, 2H)3.13 (br d, J=6.60 Hz, 2H), LC-MS: tR (min) 5.66 (20-100% ACN with 0.1%TFA 6 min), m/z [M+H]⁺ C₁₆H₁₃F₂N₃O₂ requires: 317.1, found: 318.1. HPLCtR (min) 6.89, 98.1% (10-100% ACN with 0.1% TFA 10 min).

The methods described in Example 17 were also used to prepareII-3, II-8,and II-9.

Example 18. Preparation of1-((2-cyclopropylpyridin-4-yl)methyl)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one(Compound II-15)

Step 1: methyl 2-cyclopropylpyridine-4-carboxylate

A mixture of methyl 2-bromopyridine-4-carboxylate (5.0 g, 23.14 mmol),tricyclohexylphosphine (649 mg, 2.31 mmol), cyclopropylboronic acid (3.0g, 34.72 mmol), potassium phosphate (17 g, 81.01 mmol) and palladiumacetate (260 mg, 1.16 mmol) in toluene (140 mL) and water (28 mL) wasstirred at 100° C. for 16 hours under nitrogen atmosphere. After cooled,the reaction mixture was diluted with water (100 mL) and ethyl acetate(100 mL). The separated organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 100-200 mesh, 0-10% ethylacetate in petroleum ether) to afford methyl2-cyclopropylpyridine-4-carboxylate (1.33 g, 30%) as light yellow oil.

Step 2: (2-cyclopropyl-4-pyridyl)methanol

To a solution of methyl 2-cyclopropylpyridine-4-carboxylase (1.3 g, 7.48mmol) and sodium methoxide (20 mg, 0.37 mmol) in methanol (20 mL) wasadded sodium borohydride (851 mg, 22.49 mmol) at 0° C. After stirred at80° C. for 16 hours, the reaction mixture was diluted with water (50 mL)and ethyl acetate (50 mL). The separated organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-50% ethyl acetate in petroleum ether) to afford(2-cyclopropyl-4-pyridyl)methanol (690 mg, 62%) as colorless oil.

Step 3:1-((2-cyclopropylpyridin-4-yl)methyl)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2(1H)-one(Compound II-15)

To a solution of (2-cyclopropyl-4-pyridyl)methanol (42 mg, 0.28 mmol),4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one (II-12, 50mg, 0.23 mmol), triphenylphosphine (123 mg, 0.47 mmol) intetrahydrofuran (3 mL) was added diisopropylazodicarboxylate (95 mg,0.47 mmol) at 0° C. After stirred at 20° C. for 16 hours, the reactionmixture was diluted with water (30 mL) and ethyl acetate (30 mL). Theseparated organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by RP-HPLC(10-40% acetonitrile in water and 0.04% ammonium hydroxide and 10 mMammonium bicarbonate) to afford1-[(2-cyclopropyl-4-pyridyl)methyl]-4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-one(11 mg, 13%) as a yellow solid.

Example 19. Synthesis of N-Alkyl Ether Pyridinone Compounds of Formula(I) Preparation of4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-(3,5-difluorophenoxy)ethyl)pyridin-2(1H)-one(Compound II-14)

Step 1: 1-(2-bromoethoxy)-3,5-difluoro-benzene

To a solution of 3,5-difluorophenol (500 mg, 3.84 mmol) and1,2-dibromoethane (4.4 g, 23.54 mmol) in acetonitrile (10 mL) was addedpotassium carbonate (712 mg, 5.15 mmol). The mixture was stirred at 75°C. for 16 hours and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by column chromatography(silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) toafford 1-(2-bromoethoxy)-3,55-difluoro-benzene (174 mg, 19%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.58-6.34 (m, 3 H), 4.26 (t,J=6.40 Hz, 2H), 3.64 (t, J=6.0 Hz, 2H).

Step4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[2-(3,5-difluorophenoxy)ethyl]pyridin-2-one(Compound II-14)

To a solution of4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one (II-12, 40mg, 0.19 mmol) and 1-(2-bromoethoxy)-3,5-difluoro-benzene (53 mg, 0.23mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (78mg, 0.56 mmol). The mixture was stirred at 25° C. for 16 hours andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by RP-HPLC (49-79% acetonitrile in water and 0.225%formic acid) to afford4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[2-(3,5-difluorophenoxy)ethyl]pyridin-2-one(23.4 mg, 34%) as a white solid.

The methods disclosed in Example 19 were also used to prepare CompoundsII-13 and II-16.

Example 20. Preparation of5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-(3-fluorophenoxy)ethyl)pyridazin-3(2H)-one(Compound II-17)

Step 1: ethyl 6-oxo-1H-pyridazine-4-carboxylate

To a solution of 6-oxo-1H-pyridazine-4-carboxylic acid (5.5 g, 39.26mmol) in ethyl alcohol (50 mL) was added concentrated sulfuric acid(98%, 10.1 g, 101.12 mmol). After stirred at 80° C. for 48 hours undernitrogen atmosphere, the mixture was concentrated under reducedpressure. The residue was adjusted to pH=8 by addition of saturatedaqueous sodium carbonate and extracted with ethyl acetate (100 mL×3).The combined organic layers were dried over sodium sulphate andconcentrated to dryness under reduced pressure to afford crude ethyl6-oxo-1H-pyridazine-4-carboxylate (3 g, 45%) as a brown solid.

Step 2: ethyl6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate

To a solution of ethyl6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate (3.0 g,17.84 mmol) in N,N-dimethylformamide (20 ml,) was addedN,N-diisopropylethylamine (3.7 g, 28.55 mmol) and(2-(chloromethoxy)ethyl)trimethylsilane (5.9 g, 35.68 mmol). Afterstirred at 20° C. for 32 hours, the reaction mixture was diluted withwater (30 mL) and ethyl acetate (100 mL). The separated organic extractwas washed with brine (50 mL×3), dried over sodium sulphate andconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetatein petroleum ether) to afford ethyl6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate (2.9 g,42%) as yellow oil.

Step 3:6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carbohydrazide

To a solution of ethyl6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carboxylate (2.9 g,9.72 mmol) in ethyl alcohol (50 mL) was added hydrazine hydrate (85%,6.2 g, 105.10 mmol). After stirred at 80° C. for 3 hours, the mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 100-200 mesh, 0-10% dichloromethanein methanol) to afford6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carbohydrazide (2.5g, 90%) as a yellow solid.

Step 4:5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one

To a solution of6-oxo-1-(2-trimethylsilylethoxymethyl)pyridazine-4-carbohydrazide (2.5g, 8.79 mmol) and N,N-diisopropylethylamine (9.1 g, 70.33 mmol) intetrahydrofuran (30 mL) was added (2,2-difluoroacetyl)2,2-difluoroacetate (6.1 g, 35.16 mmol) dropwise at 0° C. After stirredat 20° C. for 1 hour, the mixture was warm to 70° C. and stirred for 1hour. The reaction mixture was diluted with water (150 mL) and extractedwith ethyl acetate (150 mL×3). The combined organic layers were driedover sodium sulphate and concentrated to dryness under reduced pressure.The residue was purified by column chromatography (silica gel, 100-200mesh, 0-5% methanol in dichloromethane) to afford5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one(1.27 g, 40%) as a brown solid.

Step 5: 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridazin-6-one

To a solution of5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(2-trimethylsilylethoxymethyl)pyridazin-3-one(1.3 g, 3.69 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (10 mL) wasadded trifluoroacetic acid (4.2 g, 36.88 mmol.). After stirred at 20° C.for 1 h, the mixture was concentrated under reduced pressure. Theresidue was diluted with water (50 mL) and adjusted pH=8 by addition ofaqueous saturated sodium bicarbonate. The mixture was extracted withdichloromethane (50 mL×3). The combined organic layers were dried oversodium sulphate and concentrated to dryness under reduced pressure. Theresidue was purified by column chromatography (silica gel, 100-200 mesh,0-5% methanol in dichloromethane) to afford4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridazin-6-one (571 mg,59%) as a yellow solid.

Step 6:5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[2-(3-fluorophenoxy)ethyl]pyridazin-3-one(Compound II-17)

To a solution of 1-(2-bromoethoxy)-3-fluoro-benzene (56 mg, 0.26 mmol)in N,N-dimethylformamide (1 mL) was added sodium carbonate (49 mg, 0.47mmol) and 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridazin-6-one(50 mg, 0.23 mmol). The mixture was stirred at 20° C. for 1 hour andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by RP-HPLC (30-60% acetonitrile in water and 0.225%formic acid) to afford5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[2-(3-fluorophenoxy)ethyl]pyridazin-3-one(19.2 mg, 23%) as a white solid.

Example 21. Preparation of4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[[(1R,2R)-2-phenylcyclopropyl]methyl]pyridin-2-one(Compound II-19)

Step 1: [(1R,2R)-2-phenylcyclopropyl]methanol

To a solution of ethyl (1R,2R)-2-phenylcyclopropanecarboxylate (500 mg,2.63 mmol) in tetrahydrofuran (25 mL) was added diisobutylaluminiumhydride (1 M in tetrahydrofuran, 5.3 mL, 5.3 mmol) at 0° C. Afteraddition, the reaction mixture was warmed to 20° C. and stirred for 16hours. The reaction was quenched by addition of saturated ammoniumchloride solution (30 mL) and extracted with ethyl acetate (40 mL×3).The combined organic extracts were dried over sodium sulphate andconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetatein petroleum ether) to afford [(1R,2R)-2-phenylcyclopropyl]methanol (301mg, 77%) as colorless oil.

Step 2: [(1R,2R)-2-(iodomethyl)cyclopropyl]benzene

To a solution of [(1R,2R)-2-phenylcyclopropyl]methanol (160 mg, 1.08mmol) in tetrahydrofuran (5 mL) was added iodine (411 mg, 1.62 mmol),imidazole (220 mg, 3.24 mmol) and triphenylphosphane (850 mg, 3.24mmol). The reaction mixture was stirred at 25° C. for 0.5 hour andconcentrated to dryness under reduced pressure. The residue was purifiedby RP-TLC (petroleum ether) to afford[(1R,2R)-2-(iodomethyl)cyclopropyl]benzene (54 mg, 19%) as a whitesolid.

Step 3:4[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[[(1R,2R)-2-phenylcyclopropyl]methyl]pyridin-2-one(Compound II-19)

To a solution of [(1R,2R)-2-(iodomethyl)cyclopropyl]benzene (54 mg, 0.21mmol) and 4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one(37 mg, 0.17 mmol) in N,N-dimethylformamide (1 mL) was added potassiumphosphate (72 mg, 0.52 mmol). The mixture was stirred at 25° C. for 16hours and filtered. The filtrate was concentrated to dryness underreduced pressure. The residue was purified by RP-HPLC (50-80%acetonitrile in water and 0.225% formic acid) to afford4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1-[[(1R,2R)-2-phenylcyclopropyl]methyl]pyridin-2-one(5.6 mg, 9%) as a yellow solid.

Example 22. PreparationN-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)ethanesulfonamide(Compound IVb-1)

Step 1:(1E)-2-chloroacetaldehyde oxime

To a solution of 2-chloroacetaldehyde (14.5 g, 73.8 mmol, 40% purity) inwater (50 mL) was added sodium acetate (7.3 g, 88.6 mmol) andhydroxylamine hydrochloride (6.2 g, 88.6 mmol). After stirred at 20° C.for 1 hour, the reaction was quenched by addition of saturated sodiumbicarbonate (20 mL). The mixture was extracted with ethyl acetate (100mL×2). The combined organic extracts were dried over sodium sulphate andconcentrated to dryness under reduced pressure to afford(1E)-2-chloroacetaldehyde oxime (4.0 g, 58%) as a yellow solid which wasused in next step without further purification.

Step 2: ethyl 3-(chloromethyl)isoxazole-5-carboxylate

To a solution of (1E)-2-chlomacetaldehyde oxime (4.0 g, 42.8 mmol) intetrahydrofuran (15 mL) was added ethyl prop-2-ynoate (4.2 g, 42.8 mmol)and sodium hypochlorite (181.5 g, 243.8 mmol, 10% purity) at 0° C. Afterstirred at 20° C. for 18 hours, the reaction mixture was diluted withethyl acetate (200 mL) and brine (200 mL). The separated organic layerwas dried over sodium sulphate and concentrated to dryness under reducedpressure. The residue was purified by column chromatography (silica gel,100-200 mesh, 0-10% ethyl acetate in petroleum ether) to afford ethyl3-(chloromethyl)isoxazole-5-carboxylate (2.8 g, 35%) as a white solid.

Step 3: ethyl3-[(3-chloro-N-ethylsulfonyl-anilino)methyl]isoxazole-5-carboxylate

To a solution of N-(3-chlorophenyl)ethanesulfonamide (461 mg, 2.10 mmol)in N,N-dimethylformamide (5 mL) was added ethyl3-(chloromethyl)isoxazole-5-carboxylate (200 mg, 1.05 mmol) and sodiumcarbonate (334 mg, 3.15 mmol). After stirred at 30° C. for 16 hours, themixture was diluted with ethyl acetate (50 mL) and washed with brine (50mL×2). The separated organic layer was dried over sodium sulphate andconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetatein petroleum ether) to afford ethyl3-[(3-chloro-N-ethylsulfonyl-anilino)methyl]isoxazole-5-carboxylate (370mg, 95%) as a white solid.

Step 4:N-(3-chlorophenyl)-N-[[5-(hydrazinecarbonyl)isoxazol-3-yl]methyl]ethanesulfonamide

To a solution of ethyl3-[(3-chloro-N-ethylsulfonyl-anilino)methyl]isoxazole-5-carboxylate (170mg, 0.46 mmol) in ethanol (2 mL) was added hydrazine hydrate (250 mg,4.89 mmol). The mixture was stirred at 60° C. for 2 hours andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-10% methanol indichloromethane) to affordN-(3-chlorophenyl)-N-[[5-(hydrazinecarbonyl)isoxazol-3-yl]methyl]ethanesulfonamide(100 mg, 61%) as a white solid.

Step 5:N-(3-chlorophenyl)-N-[[5-[[(-difluoroacetyl)amino]carbamoyl]-isoxazol-3-yl]methyl]ethanesulfonamide

To a solution ofN-(3-chlorophenyl)-N-[[5-(hydrazinecarbonyl)isoxazol-3-yl]methyl]ethanesulfonamide(100 mg, 0.28 mmol) and N,N-diisopropylethylamine (36 mg, 0.28 mmol) intetrahydrofuran (2 mL) was added (2,2-difluoroacetyl)2,2-difluoroacetate (49 mg, 0.28 mmol) under nitrogen atmosphere. Afterstirred at 20° C. for 2 hours, the reaction was quenched by addition ofwater (50 mL) and extracted with ethyl acetate (30 mL×3). The combinedorganic layers were dried over sodium sulphate and concentrated todryness under reduced pressure. The residue was purified by RP-TLC(petroleum ether:ethyl acetate=1:1) to affordN-(3-chlorophenyl)-N-[[5-[[(2,2-difluoroacetyl)amino]carbamotl]isoxazol-3-yl]methyl]ethanesulfonamide (110 mg, 90%) as a white solid.

Step 6:N-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)ethanesulfonamide(Compound IVb-1)

To a solution ofN-(3-chlorophenyl)-N-[[5-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-3-yl]methyl]ethanesulfonamide(100 mg, 0.23 mmol) in tetrahydrofuran (2 mL) was added. Burgess reagent(136 mg, 0.57 mmol). The mixture was stirred at 90° C. for 2 hours undernitrogen atmosphere and concentrated under reduced pressure. The residuewas purified by RP-HPLC (35 to 65% acetonitrile in water and 0.1%trifluoroacetic acid) to affordN-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]isoxazol-3-yl]methyl]ethanesulfonamide (13 mg, 13%) as a white solid.

Example 23. Preparation ofN-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-(pyridin-3-yl)ethane-1-sulfonamide(IVa-2)

Step 1: ethyl5-[[ethylsulfonyl(3-pyridyl)amino]methyl]isoxazole-3-carboxylate

To a solution of ethyl5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate (400 mg, 1.23 mmol)and N-(3-pyridyl)ethanesulfonamide (275 mg, 1.48 mmol) inN,N-dimethylformamide (8 mL) was added sodium carbonate (391 mg, 3.69mmol) and potassium iodide (20 mg, 0.12 mmol) at 20° C. After stirringat 20° C. for 16 h, the residue was diluted with ethyl acetate (10 mL)and washed with brine (3×10 mL). The organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure. Theresidue was purified by flash column chromatography (silica gel, 100-200mesh, 0-6% methanol in dichloromethane) to afford ethyl5-[[ethylsulfonyl(3-pyridyl)amino]methyl]isoxazole-3-carboxylate (323mg, 75%) as a light yellow solid.

Step 2:N-[[3-(hydrazinecarbonyl)isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulforamide

To a solution of ethyl5-[[ethylsulfonyl(3-pyridyl)amino]methyl]isoxazole-3-carboxylate (273mg, 0.80 mmol) in ethanol (3 mL) was added hydrazine hydrate (403 mg,8.04 mmol). The mixture was stirred at 60° C. for 1 h and concentratedto dryness under reduced pressure. The residue was purified by flashcolumn chromatography (silica gel, 100-200 mesh, 0-10% methanol indichloromethane) to affordN-[[3-(hydrazinecarbonyl)isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide(204 mg, 75%) as light yellow oil.

Step 3:N-[[3-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide

To a solution ofN-[[3-(hydrazinecarbonyl)isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide(184 mg, 0.56 mmol) in tetrahydrofuran (3 mL) was addedN-ethyl-N-isopropylpropan-2-amine (80 mg, 0.62 mmol) and(2,2-difluoroacetyl) 2,2-difluoroacetate (118 mg, 0.69 mmol). Afterstirring at 20° C. for 1 h, the reaction mixture quenched by addition ofwater (5 mL) and extracted with ethyl acetate (2×10 mL). The combinedorganic extracts were dried over anhydrous sodium sulphate andconcentrated to dryness under reduced pressure. The residue was purifiedby flash column chromatography (silica gel, 100-200 mesh, 0-10% methanolin dichloromethane) to affordN-[[3-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide(200 mg, 70%) as a colorless oil.

Step 4:N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-(pyridin-3-yl)ethane-1-sulfonamide

To a solution ofN-[[3-[[(2,2-difluoroacetyl)amino]carbamoyl]isoxazol-5-yl]methyl]-N-(3-pyridyl)ethanesulfonamide(100 mg, 0.25 mmol) in tetrahydrofuran (2 mL) was added Burgess reagent(148 mg, 0.62 mmol). The mixture was stirred at 90° C. for 3 h andcooled. The solution was diluted with water (4 mL) and extracted withethyl acetate (2×10 mL). The combined organic extracts were dried overanhydrous sodium sulphate and concentrated to dryness under reducedpressure. The residue was purified by preparative TLC(dichloromethane:methanol=20:1) to affordN-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-(pyridin-3-yl)ethane-1-sulfonamide(20.3 mg, 21%) as a white solid.

The method disclosed in Example 23 was also used to prepare CompoundsIVa-3 and IVa-4.

Example 24. Preparation of3-chloro-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)-N-methylaniline(Compound IVb-2)

Step 1: ethyl3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carboxylate

To a solution of ethyl 3-(chloromethyl)isoxazole-5-carboxylate (300 mg,1.58 mmol) in N,N-dimethylformamide (10 mL) was added3-chloro-N-methyl-aniline (291 mg, 2.06 mmol), sodium carbonate (503 mg,4.75 mmol) and potassium iodide (26 mg, 0.16 mmol). The reaction mixturewas stirred at 25° C. for 2 hours and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate inpetroleum ether) to afford ethyl3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carboxylate (270 mg,54%).

Step 2: 3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carbohydrazide

To a solution of ethyl3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carboxylate (220 mg,0.75 mmol) in ethyl alcohol (4 mL) was added hydrazine hydrate (440 mg,7.46 mmol, 85% purity). The reaction mixture was stirred at 60° C. for 2hours and concentrated under reduced pressure. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0-5% methanol indichloromethane) to afford3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carbohydrazide (150 mg,68%) as yellow oil.

Step 3:3-[(3-chloro-N-methyl-anilino)methyl]-N′-(2,2-difluoroacetyl)isoxazole-5-carbohydrazide

To a solution of3-[(3-chloro-N-methyl-anilino)methyl]isoxazole-5-carbohydrazide (150 mg,0.53 mmol) in tetrahydrofuran (3 mL) was addedN-ethyl-N-isopropylpropan-2-amine (69 mg, 0.53 mmol) and(2,2-difluoroacetyl) 2,2-difluoroacetate (112 mg,0.64 mmol). The mixturewas stirred at 20° C. for 2 hours and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,100-200 mesh, 0-50% ethyl acetate in petroleum ether) to afford3-[(3-chloro-N-methyl-anilino)methyl]-N′-(2,2-difluoroacetyl)isoxazole-5-carbohydrazide(150 mg, 74%) as a yellow solid.

Step 4:3-chloro-N-[[5-[5-(difluoromethyl)-1,3,4-oxadisoxazol-2-yl]isoxazol-3-yl]methyl]-N-methyl-aniline(Compound IVb-2)

To a solution of 3-[(3-chloro-N-methyl-anilino)methyl]-N′-(2,2-difluoroacetyl)isoxazole-5-carbohydrazide(50 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was added Burgess reagent(83 mg, 0.35 mmol). The mixture was stirred at 90° C. for 3 hours in amicrowave reactor and filtered. The filtrate was concentrated underreduced pressure. The residue was purified by RP-HPLC (40-70%acetonitrile in water and 0.04% ammonium hydroxide and 10 mM ammoniumbicarbonate) to afford3-chloro-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-tl]isoxazol-3-yl]methyl]-N-methyl-aniline(7.2 mg, 15%).

The method disclosed in Example 24 was also used to prepare CompoundIVb-3.

Example 25. Preparation of3-chloro-N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-tl}methyl)-N-methylaniline(IVa-1)

Step 1: ethyl 5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate

To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (2.0 g,11.69 mmol) in dichloromethane (50 mL) was added triethylamine (1.3 g,12.85 mmol) and 4-methylbenzenesulfonyl chloride under nitrogenatmosphere. After stirring at 20° C. for 3 h, the reaction mixture wasdiluted with dichloromethane (30 mL) and washed with brine (50 mL). Theorganic layer was dried over anhydrous sodium sulphate and concentratedunder reduced pressure. The residue was purified by flash columnchromatography (silica gel, 100-200 mesh, 0-25% ethyl acetate inpetroleum ether) to afford ethyl5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate (2.54 g, 64%) as awhite solid.

Step 2: ethyl5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carboxylate

To a solution of ethyl5-(p-tolylsulfonyloxymethyl)isoxazole-3-carboxylate (400 mg, 1.23 mmol)and 3-chloro-N-methyl-aniline (209 mg, 1,48 mmol) inN,N-dimethylformamide (8 mL) was added sodium carbonate (391 mg, 3.69mmol) and potassium iodide (20 mg, 0.12 mmol). After stirring at 20° C.for 16 h, the mixture was diluted with ethyl acetate (10 mL) and washedwith brine (3×10 mL). The organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure. The residue waspurified by flash column chromatography (silica gel, 100-200 mesh, 0-25%ethyl acetate in petroleum ether) to afford ethyl5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carboxylate (230 mg,59%) as a white solid.

Step 3: 5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carbohydrazide

To a solution of ethyl5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carboxylate (180 mg,0.61 mmol) in ethanol (3 mL) was added hydrazine hydrate (360 mg, 6.11mmol). The mixture was stirred at 60° C. for 1 h and concentrated todryness under reduced pressure. The residue was purified by flash columnchromatography (silica gel, 100-200 mesh, 0-5% methanol indichloromethane) to afford5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carbohydrazide (181 mg,88%) as a light yellow oil.

Step 4:5-[(3-chloro-N-methyl-anilino)methyl]-N-(2,2-difluoroacetyl)isoxazole-3-carbohydrazide

To a solution of5-[(3-chloro-N-methyl-anilino)methyl]isoxazole-3-carbohydrazide (181 mg,0.64 mmol) in tetrahydrofuran (3 mL) was addedN-ethyl-N-isopropylpropan-2-amine (92 mg, 0.71 mmol) and(2,2-difluoroacetyl) 2,2-difluoroacetate (135 mg, 0.77 mmol) undernitrogen atmosphere. After stirring at 20° C. for 1 hour, the reactionmixture was quenched by addition of water (5 mL) and extracted withethyl acetate (2×10 mL). The combined organic extracts were dried overanhydrous sodium sulphate and concentrated to dryness under reducedpressure. The residue was purified by flash column chromatography(silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) toafford5-[(3-chloro-N-methyl-anilino)methyl]-N′-(2,2-difluoroacetyl)isoxazole-3-carbohydrazide(148 mg, 62%) as a white solid.

Step 5:3-chloro-N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-methylaniline

To a solution of 5-[(3-chloro-N-methyl-anilino)methyl]-N′-(2,2-difluoroacetyl)isoxazole-3-carbohydrazide(72 mg, 0.20 mmol) in tetrahydrofuran (2 mL) was added Burgess reagent(120 mg, 0.50 mmol). The mixture was stirred at 90° C. for 3 h andcooled. The solution was diluted with water (4 mL) and extracted withethyl acetate (2×10 mL). The combined organic extracts were dried overanhydrous sodium sulphate and concentrated to dryness under reducedpressure. The residue was purified by preparative TLC (petroleumether:ethyl acetate=3 1) to afford3-chloro-N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-methylaniline(22.2 mg, 27%) as a light yellow oil.

Example 26. Preparation of5-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole-2-carbonitrile(A-1)

Step 1:5-bromo-N-(1-(2,6-difluorophenyl)cyclopropyl)-3-fluoropyridin-2-amine

To a vial was added 1-(2,6-difluorophenyl)cyclopropan-1-amine (304 mg,1.80 mmol),,DMSO (3 mL), DIPEA (1.57 mL, 9.0 mmol, 5 equiv), and5-bronco-2,3-difluoropyridine (0.29 mL, 2.2 mmol, 1.2 equiv). Thebiphasic homogeneous mixture was heated to 120° C. overnight under N₂atmosphere (balloon). Upon reaching 120° C., the reaction becomesmonophasic. The following day, LCMS analysis of the dark brown mixturereveals full conversion of the amine partner. The reaction was worked upby pouring into water (50 mL) and extracting three times with EtOAc (30mL each). The combined organic layers were washed twice with water andonce with brine, then dried over MgSO₄, filtered and concentrated byrotary evaporation. The crude product, a brown oil, was dry-loaded ontosilica gel and purified by column chromatography (Silica gel, 0-25%EtOAc/hexanes) to afford the title compound as a pale-yellow oil, 400 mg(65%).

Step 2: methyl6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinate

5-Bromo-N-(1-(2,6-difluorophenypcyclopropyl)-3-fluoropyridin-2-amine(686 mg, 2 mmol), Pd(OAc)₂ (22 mg, 0.1 mmol) and Xantphos (115 mg, 0.2mmol) were dissolved in MeOH (6.5 mL) and Et₃N (35 mL) mixture. Aballoon with carbon monoxide was attached and the gas was bubbledthrough the solution for 1 minute. The reaction mixture with attachedcarbon monoxide balloon was heated at 70° C. overnight. The reactionmixture was cooled to rt, evaporated, diluted with MeOH, preadsorbed onsilica gel and purified by column chromatography (silica gel; hex/EtOAc1:0 gradient to 4:1) to give 525 mg (81%) of product.

Step 3: 6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinicacid

A LiOH solution (1.5 mmol, 1.5 mL, 1M in water) was added to a stirredsolution of methyl6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinate (161 mg,0.5 mmol) in THF (2 mL). The reaction mixture was stirred at 70° C. for3 hours, cooled to rt and acidified with HCl solution (1M in water). Thereaction mixture was diluted with EtOAc and washed with water (2×) andbrine. Organic fraction was dried with anhydrous Na₂SO₄ and evaporatedto give 170 mg (quantitative yield) of product.

Step 4:2-(2-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinoyl)hydrazineyl)-2-oxoacetamide

HOBt (4 mg, 0.025 mmol) was added to a solution of6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinic acid (154mg, 0.5 mmol) and 2-hydrazineyl-2-oxoacetamide (77 mg, 0.75 mmol) in DMF(5 mL) and the reaction mixture was stirred at rt for 15 min.1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg,0.75 mmol) was added in one portion and the reaction mixture was heatedat 50° C. for 3 hours. The reaction mixture was cooled to rt, dilutedwith water and extracted with EtOAc (3×). Combined organic fractionswere dried with anhydrous Na₂SO₄. The solvent was evaporated, and thecrude product was purified by column chromatography (silica gel;CH₂Cl₂/MeOH; 19:1 gradient to 3:1) to give 149 mg of product that wascontaminated with DMF. Trituration from CHCl₃ gave 81 mg (41%) of purematerial.

Step 5:5-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole-2-carbonitrile

A solution of2-(2-(6-((1-(2,6-difluorophenyl)cyclopropyl)amino)-5-fluoronicotinoyl)hydrazineyl)-2-oxoacetamide(61 mg, 0.16 mmol) in POCl₃ (3 mL) was stirred at 100° C. for 6 hours.The reaction mixture was cooled to rt, POCl₃ was evaporated and theresidue was dissolved in EtOAc. This solution was poured into saturatedNaHCO₃ solution and layers were separated. Organic fraction was driedwith anhydrous Na₂SO₄. The solvent was evaporated, and the crude productwas purified by column chromatography (silica gel; hexane/EtOAc 1:0gradient to 7:3) to give 18 mg (33%) of product.

Example 27. Preparation of1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-5-phenylpyrrolidin-2-one(Compound A-2)

Step 1: ethyl 2-benzylpyrazolo[1,5-a]pydmidine-6-carboxylate

To a solution of ethyl 2-formyl-3-oxo-propanoate (247 mg, 1.71 mmol) inethanol (5 mL) was added 3-benzyl-1H-pyrazol-5-amine (300 mg, 1.73mmol). The mixture was stirred at 80° C. for 2 hours. The reaction wasquenched by addition of saturated sodium bicarbonate (50 mL) andextracted with ethyl acetate (50 mL×2). The combined organic layers weredried over sodium sulphate and concentrated to dryness under reducedpressure. The residue was purified by column chromatography (silica gel,100-200 mesh, 0-20% ethyl acetate in petroleum ether) to afford ethyl2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylate (205 mg, 42%) as a whitesolid.

Step 2: 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid

To a solution of ethyl 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylate(200 mg, 0.71 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was addedlithium hydroxide monohydrate (60 mg, 1.42 mmol). The mixture wasstirred at 20° C. for 2 hours and adjusted to pH=4 by addition ofhydrochloric acid (1 M). The resulting mixture was extracted with ethylacetate (30 mL×3). The combined organic extracts were dried over sodiumsulphate and concentrated to dryness under reduced pressure to affordcrude 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (180 mg,crude) as a white solid.

Step 3: tert-butylN-[(2-benzylpyrazolo[1,5-a]pyrimidine-6-carbonyl)-amino]carbamate

To a solution of 2-benzylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid(130 mg, 0.51 mmol) in dichloromethane (5 mL) was added HATU (234 mg,0.61 mmol) and N-ethyl-N-isopropylpropan-2-amine (100 mg, 0.77 mmol).After stirred at 0° C. for 15 minutes, tert-butyl N-aminocarbamate (75mg, 0.56 mmol) was added. After stirred at 20° C. for 16 hours, thereaction mixture was diluted with ethyl acetate (50 mL) and brine (50mL). The separated organic extract was dried over sodium sulphate andconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetatein petroleum ether) to afford tert-butylN-[(2-benzylpyrazolo[1,5-a]pyrimidine-6-carbonyl)amino]carbamate (185mg, 98%) as a white solid.

Step 4: 2-benzylpyrazolo[1,5-a]pyrimidine-6-carbohydrazide

A solution of tert-butylN-[(2-benzylpyrazolo[1,5-a]pyrimidine-6-carbonyl)amino]carbamate (150mg, 0.48 mmol) in hydrochloric acid (4 M in methanol, 5 mL) was stirredat 20° C. for 2 hours and concentrated to dryness under reducedpressure. The residue was diluted with ethyl acetate (50 mL) and addedsodium bicarbonate (200 mg). The resulting mixture was stirred for 30minutes and filtered. The filtrate was concentrated to dryness underreduced pressure. The residue was purified by RP-TLC(dichloromethane:methanol=10:1) to afford2-benzylpyrazolo[1,5-a]pyrimidine-6-carbohydrazide (35 mg, 32%) as awhite solid.

Step 5:2-benzyl-N′-(2,2-difluoroacetyl)pyrazolo[1,5-a]pyrimidine-6-carbohydrazide

To a solution of 2-benzylpyrazolo[1,5-a]pyrimidine-6-carbohydrazide (35mg, 0.13 mmol) in tetrahydrofuran (5 mL) was addedN-ethyl-N-isopropylpropan-2-amine (17 mg, 0.13 mmol) and(2,2-difluoroacetyl) 2,2-difluoroacetate (27 mg, 0.16 mmol). Afterstirred at 20° C. for 1 hour, the reaction mixture was concentrated todryness under reduced pressure. The residue was purified by RP-TLC(petroleum ether:ethyl acetate=1:1) to afford2-benzyl-N′-(2,2-difluoroacetyl)pyrazolo[1,5-a]pyrimidine-6-carbohydrazide(35 mg, 77%) as a white solid.

Step 6: 2-(2-benzylpyrazolo[1,5-a]pyrimidn-6-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (Compound A-2)

To a solution of2-benzyl-N′-(2,2-difluoroacetyl)pyrazolo[1,5-a]pyrimidine-6-carbohydrazide(35 mg, 0.10 mmol) in tetrahydrofuran (2 mL) was added Burgess reagent(109 mg, 0.46 mmol). The mixture was stirred at 90° C. for 3 hours in amicrowave reactor under nitrogen atmosphere. The mixture was filteredand the filtrate was concentrated to dryness under reduced pressure. Theresidue was purified by RP-HPLC (30-60% acetonitrile in water and 0.225%formic acid) to afford2-(2-benzylpyrazolo[1,5-a]pyrimidin-6-yl)-5-(difluoromethyl)-1,3,4-oxadiazole(2.7 mg, 8%) as a white solid.

Biochemical Assay The compounds disclosed herein were tested for potencyagainst HDAC6 and selectivity against HDAC1 in a biochemical assay. Abiochemical assay was adopted using a luminescent HDAC-Glo I/II assay(Promega) and measured the relative activity of HDAC6 and HDAC1recombinant proteins. Compounds were first incubated in the presence ofHDAC6 or HDAC1 separately, followed by addition of the luminescentsubstrate. The data was acquired using a plate reader and thebiochemical IC₅₀ were calculated from the data accordingly. Data istabulated in Table 3 and Table 4. From these studies, it was determinedthat the compounds of the present disclosure are selective inhibitors ofHDAC6 over HDAC1, providing selectivity ratios from about 5 to about30,0000.

TABLE 3 Characterization Data and HDAC6 Activity for Compounds ofFormula (I). HDAC6 Cmpd ¹H NMR IC₅₀ ID/Prep Stracture/Name MS (m/z) (RT)(μM) I-1 Example 2

  4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 8.01-8.05 (m, 1 H), 7.29 (dd, J = 8.1, 1.5 Hz, 1 H),7.01 (dd, J =8.1 1.5 Hz, 1H), 6.89 (t, J = 51.6 Hz, 1 H), 5.70 (s, 2 H) LCMS: RT =5.00 min, m/z = 394.0 0.107 I-2 Example 4

  N-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1 H),7.48 (s, 1 H), 7.32-7.40 (m, 3 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.25 (s,2 H) 3.07 (s, 3 H) LCMS: RT = 4.83 min, m/z = 421.0 0.021 I-3 Example 4

  N-(3-chlorophenyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1 H),7.48 (s, 1 H), 7.25-7.40 (m, 3 H), 6.19 (t, J = 51.6 Hz, 1 H), 5.28 (s,2 H), 3.18 (q, J = 7.6 Hz, 2 H), 1.44 (t, J = 7.2 Hz, 3 H) LCMS: RT =4.90 min, m/z = 435.0 0.0044 I-4 Example 4

  N-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s,1 H), 7.40-7.70 (m, 5 H), 5.43 (s, 2 H), 2.95-3.00 (m, 1 H), 1.00-1.05(m, 2 H), 0.90-0.95 (m, 2 H) LCMS: RT = 5.10 min, m/z = 447.0 0.0042 I-5Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(3,4- difluorophenyl)ethanesulfonamide ¹H NMR(400 MHz, DMSO-d₆) δ 8.38 (s, 1 H), 7.30-7.40 (m, 1 H), 7.15- 7.25 (m, 2H), 6.91 (t, J = 51.2 Hz, 1 H), 5.24 (s, 2 H), 3.17 (q, J = 7.6 Hz, 2H), 1.44 (t, J = 5.7 Hz, 3 H) LCMS: RT = 4.92 min, m/z = 437.0 0.016 I-6Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3- yl)ethanesulfonamide ¹H NMR (400MHz, CDCl₃) δ 8.71 (br s, 1 H) 8.58 (br s, 1 H), 8.38 (s, 1 H) 7.80-7.85(m, 1 H), 7.31-7.35 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.30 (s, 2 H),3.21 (q, J = 7.2 Hz, 2 H), 1.46 (t, J = 7.6 Hz, 1 H) LCMS: RT = 3.39min, m/z = 402.0 0.029 I-7 Example 5

  N-((5-(5-(difluoromethyl-1,3,4-oxadiazol-2- yl)thiazol-2-yl)methyl)-3-(trifluoromethyl)aniline ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1 H) 7.52(t, J = 51.2 Hz, 1 H) 7.22-7.35 (m, 2 H) 6.89-6.87 (m, 3 H) 4.80 (d, J =6.1 Hz, 2 H) LCMS: RT 5.20 min, m/z = 377.0 0.222 I-8 Example 6

  N-((5-(5-(difluoromethyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(3- (trifluoromethyl)phenyl)nicotinamide ¹HNMR (400 MHz, CDCl₃) δ 8.50- 8.60 (m, 1 H) 8.41 (s, 1 H) 7.71 (d, J =7.8 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.35-7.45 (m, 2 H), 7.25-7.30(m, 1 H) 7.20-7.25 (m, 1 H) 6.91 (t, J = 51.6 Hz, 1 H) 5.46 (s, 2 H)LCMS: RT = 4.22 min, m/z = 482.0 0.088 I-9 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N- phenylmethanesulfonamide ¹H NMR (400 MHz,CDCl₃) δ = 8.37 (s, 1 H), 7.33-7.49 (m, 5 H), 6.90 (t, 1 H, J = 51.6 Hz)5.27 (s, 2 H), 3.05 (s, 3 H) ppm LCMS: RT = 4.42 min, m/z = 387.0 0.051I-10 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N- phenylethanesulfonamide ¹H NMR (400 MHz,CDCl₃) δ 8.35 (s, 1 H), 7.29-7.53 (m, 5 H), 6.90 (t, 1 H, J = 51.5 Hz),5.30 (s, 2 H), 3.17 (q, J = 7.34 Hz, 2 H), 1.45 (t, J = 7.46 Hz, 4 H)ppm LCMS: RT = 4.65 min, m/z = 401.0 0.026 I-12 Example 4

  N-(3-chlorophenyl-N-((5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide ¹H NMR (400 MHz, chloroform-d) δ ppm8.39 (s, 1 H) 7.51 (s, 1 H) 7.41 (br s, 1 H) 7.32 (br d, J = 3.91 Hz, 2H) 5.27 (s, 2 H) 2.48-2.59 (m, 1H) 1.10-1.17 (m, 2 H) 0.99-1.09 (m, 2 H)LCMS: RT = 5.84 min, m/z = 465 0.869 I-13 Example 4

  N-(3-chloro-4-fluorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methylmethanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1 H)7.56 (dd, J = 6.36, 2.69 Hz, 1 H) 7.32- 7.41 (m, 1 H) 7.18 (t, J = 8.56Hz, 1 H) 6.76-7.08 (m, 1 H) 5.22 (s, 2 H) 3.07 (s, 3 H) LCMS: RT = 4.93min, m/z = 438.9 0.021 I-14 Example 4

  N-(3-chloro-4-fluorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H)7.54 (dd, 1 = 6.24, 2.32 Hz, 1 H) 7.33- 7.40 (m, 1 H) 7.16 (t, J 8.68Hz, 1 H) 6.76-7.06 (m, 1 H) 5.23 (s, 2 H) 3.18 (q, J = 7.34 Hz, 2 H)1.45 (t, J = 7.34 Hz, 3 H) LCMS: RT = 5.11 min m/z = 453 0.014 I-15Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)tlhazol-2-yl)methyl)-N-(1-methyl-1H- indazol-6-yl)ethanesulfonamide¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 7.98 (d, J = 0.98 Hz, 1 H) 7.75(d, J = 8.56 Hz, 1 H) 7.60 (s, 1 H) 7.18 (d, J = 8.31 Hz, 1H) 6.75-7.05(m, 1 H) 5.39 (s, 2 H) 4.09 (s, 3 H) 3.19 (q, J = 7.17 Hz, 2 H) 1.46 (t,J = 7.46 Hz, 3 H) LCMS: RT = 4.43 min, m/z = 455.0. 0.014 I-16 Example 4

  [(3-chlorophenyl)({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazo I-2- yl}methyl)sulfamoyl]dimethylamine¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H) 7.49 (s, 1 H) 7.28-7.42 (m, 3 H)6.76- 6.06 (m, 1 H) 5.17 (s, 2 H) 2.82 (s, 6 H) LCMS: RT = 5.18 min, m/z= 450.0 0.012 I-17 Example 4

  N-cyclopropyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2- yl)methyl)ethanesulfonamide ¹H NMR (400MHz, chloroform-d) δ ppm 8.42 (s, 1 H) 6.74-7.07 (m, 1 H) 4.83 (s, 2 H)3.21 (q, J = 7.50 Hz, 2 H) 2.70 (br s, 1 H) 1.41 (t, J = 7.46 Hz, 3 H)0.83- 0.95 (m, 4 H) LCMS: RT = 4.34 min, m/z = 365.0 1.23 I-18 Example 7

  5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-(1-(2,6-difluorophenyl)cyclopropyl)thiazol- 2-amine ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.62 (br s, 1 H) 7.95 (br s, 1 H) 7.29- 7.67 (overlappingm, 2 H) 7.02-7.18 (m, 2 H) 1.35 (d, J = 26.80 Hz, 4 H) LCMS: RT = 4.87min, m/z 371.1 1.95 I-19 Example 7

  5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-N-phenethylthiazol-2-amine ¹H NMR (400 MHz, chloroform-d) δ ppm 7.86 (s,1 H) 7.16-7.46 (m, 5 H) 6.68-7.03 (m, 1H) 5.75 (brs, 1 H) 3.64 (br d, .7= 6.11 Hz, 2 H) 3.02 (br t, J = 6.85 Hz, 2 H) LCMS: RT = 4.73 min, m/z =323.0. 13.6 I-20 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1- phenylcyclopropyl)ethanesulfonamide ¹H NMR(400 MHz, CDCl₃-d₃) δ 8.78 (s, 1 H), 8.40 (s, 1 H), 7.50 (d, J = 7.34Hz, 2 H), 7.26-7.38 (m, 4 H), 7.04 (s, 0.25 H), 6.91 (s, 0.5 H), 6.78(s, 0.25 H), 4.94 (s, 2 H), 2.81 (q, J = 7.58 Hz, 2 H), 1.47 (m, 2H),1.31-1.22 (m, 5 H). LCMS: RT = 6.12, m/z = 441.1 4.14 I-21 Example 6

  1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-3,3-dimethyl-1- (pyridin-3-yl)urea ¹H NMR (400MHz, METHANOL-d4) δ ppm 9.55 (s, 1 H) 8.78 (br d, J = 5.62 Hz, 1 H)8.52-8.59 (m, 2 H) 8.06 (br d, J = 7.83 Hz, 1 H) 7.26 (t, J = 51.2 Hz, 1H) 6.33 (s, 2 H) 3.09 (s, 6 H). LCMS RT = 2.85 min, m/z = 381.1 1.2 I-22Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)ethanesulfonamide 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1 H), 8.15 (s, 1H), 7.63 (m, 1 H), 7.21 (t, J = 51.2 Hz, 1H), 6.79 (m, 1 H), 5.24 (s, 2H), 3.56 (m, 4 H), 3.25 (q, J = 7.2 Hz, 2 H), 2.51 (m, 4 H), 2.32 (s, 3H), 1.40 (t, J = 7.2 Hz, 3 H). m/z = 500,1 0.143 I-23 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6- morpholinopyridin-3-yl)ethanesulfonamide¹H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1 H), 8.18 (s, 1 H), 7.69 (m, 1 H),7.54 (t, J = 51.2 Hz, 1 H), 6.83 (m, 1 H), 5.28 (s, 1 H), 3.66 (m, 4 H),3.44 (m, 4 H), 3.30 (q, J = 6.8 Hz, 2 H), 1.29 (t, J = 6.8 Hz, 3 H). m/z= 487.1 0.417 I-24 Example 4

  methyl 3-(N-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)thiazol-2-yl)methyl)ethylsulfonamido)benzoate ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (s,1 H), 8.08 (s, 1 H), 7.95-7.83 (m, 2 H), 7.67-7.39 (m, 2 H), 5.43 (s, 2H), 3.86 (s, 3 H), 3.45-3.33 (m, 2), 1.28 (t, J = 7.21 Hz, 3 H). LCMS RT= 4.73 min, m/z = 459.1 0.031 I-25 Example 4

  tert-butyl 4-(N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2- yl)methyl)ethylsulfonamido)benzoate ¹H NMR(400 MHz, CDCl₃) δ 8.36 (s, 1 H), 8.01 (m, 2 H), 7.53 (m, 2 H), 6.91 (tJ = 51.6 Hz, 1H), 5.34 (s, 2 H), 3.21 (q, J = 7.2 Hz, 2 H), 1,57 (s, 9H), 1.43 (t, J = 7.2 Hz, 3 H). m/z = 501.1 0.101 I-26 Example 6

  methyl ((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)(pyridin-3- yl)carbamate ¹H NMR (400MHz, METHANOL-d4) δ ppm 9.55 (s, 1 H) 8.85 (br d, J = 5.87 Hz, 1 H) 8.57(s, 1 H) 8.45 (br d, J = 8.80 Hz, 1 H) 8.06-8.13 (m, 1 H) 7.26 (t, J =51.2 Hz, 1 H) 3.86 (s, 3 H). LCMS RT = 2.97 min, m/z = 368.0 2.5 I-27Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyrimidin-5- yl)ethanesulfonamide ¹H NMR (400MHz, DMSO-d₆) δ 9.12 (s, 1 H), 9.00 (s, 2 H), 8.53 (s, 1 H), 7.70-7.30(m, 1 H), 5.50 (s, 2 H), 3.55- 3.40 (m, 2 H), 1.31 (t, −7.34 Hz, 3 H).LCMS RT = 3.84 min, m/z = 403.0 0.050 I-28 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)pyridin-3-amine ¹H NMR (400 MHz, METHANOL-d4) δppm 8.58 (s, 1 H) 8.22-8.32 (m, 2 H) 7.69-7.78 (m, 2 H) 7.26 (t, J =51.2 Hz, 1H) 6.17 (s, 2 H). LCMS RT = 1.24 min, m/z = 310.1 1.5 I-29Example 4

  ¹H NMR (400 MHz, CDCl₃-d₃) δ 8.55 (s, 1 H), 8.47 (s, 1 H), 8.39 (s, 1H), 7.67 (d, J = 9.05 Hz, 1 H), 7.36-7,28 (m, 2 H), 7.19 (d, J = 6.60Hz, 2 H), 7.04-6.77 (m, 1 H) 5.22 (s, 2H), 4.25 (s, 2 H), 2.74 (s, 3 H).LCMS RT = 5.23 min, m/z = 511.1 0.041 I-30 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl-N-(6-fluoropyridin-3- yl)ethanesulfonamide ¹H NMR(400 MHz, CDCl₃) δ 8.39 (s, 1 H), 8.31 (s, 1 H), 7.94 (m, 1 H), 7.02 (m,1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.25 (s, 2 H), 3.21 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3 H). m/z = 420.0 0.011 I-31 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3- yl)propane-2-sulfonamide ¹H NMR(400 MHz, DMSO-d6) δ 8.72 (s, 1 H), 8.50 (m, 2 H), 8.02 (m, 1 H),7.40-7.66 (m, 2 H), 5.46 (s, 2 H), 3.60 (m, 1 H), 1.34 (d, J = 6.8 Hz, 6H). m/z = 416.1 0.042 I-32 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)ethanesulfonamide ¹H NMR (400 MHz, Methanol-d₄)δ 8.47 (s, 1 H), 7.96 (s, 1 H), 7.66 (d, 1 = 9.54, 1 H), 7.35 (s, 0.25H), 7.22 (s, 0.5 H), 7.09 (s, 0.25 H), 6.53 (d, J = 9.54 Hz, 1 H), 5.22(s, 2 H), 3.56 (s, 3 H), 3.35-3.30 (m, 2 H), 1.43 (t, J = 7.34 Hz, 3 H).LCMS RT = 3.53 min, m/z = 432.1 0.411 I-33 Example 4

  N-(3-chloro-4-fluorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)morpholine-4-sulfonamide ¹H NMR (400 MHz, DMSO-d6) δ 8.52(s, 1 H), 7.86-7.95 (m, 1 H), 7.35-7.69 (m, 3 H), 5.36 (s, 2 H), 3.58(m, 4 H), 3.20 (m, 4H). m/z = 510.0 0.047 I-34 Example 4

  N-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)thiomorpholine-4-sulfonamide 1,1-dioxide ¹H NMR (400 MHz,CHLOROFORM- d) δ ppm 8.41 (s, 1 H) 7.48 (s, 1 H) 7.30- 7.40 (m, 3 H)6.91 (t, J = 52.4 Hz, 1 H) 5.15 (s, 2 H) 3.73-3.82 (m, 4H) 3.05- 3.13(m, 4H). LCMS RT = 4.83 min, m/z = 540.0 0.022 I-35 Example 4

  N-(4-(1H-imidazol-1-yl)phenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide ¹H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1 H),8.27 (s, 1 H), 7.69-7.76 (m, 5 H), 7.3 (t, J = 51.2 Hz, 1 H), 7.10 (s, 1H), 5.41 (s, 2 H), 3.37 (q, J = 6.8 Hz, 2 H), 1.30 (t, J = 6.8 Hz, 3 H).m/z = 467.0 0.008 I-36 Example 4

  N-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)morpholine-4-sulfonamide ¹H NMR (400 MHz, DMSO-d6) δ 8.52(s, 1 H), 7.73 (m, 1 H), 7.54-7.58 (m, 2 H), 7.36-7.44 (m, 2 H), 5.38(s, 2 H), 3.59 (m, 4 H), 3.18 (m, 4 H). m/z = 492.1 0.005 I-37 Example 4

  ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1 H), 8.54 (d, J = 9. Hz, 2 H),8.10 (d, J = 10.0 Hz, 1 H), 7.65-7.39 (m, 1 H), 5.41 (s, 2H), 2.83 (s, 6H). LCMS RT = 4.39 min, m/z = 435.1 0.013 I-38 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-3- yl)ethanesulfonamide ¹HNMR (400 MHz, DMSO-d₆) δ 8.62- 8.52 (m, H), 8.13-8.09 (m, 1 H), 7.65-7.39 (m, 1 H), 5.46 (s, 2 H), 3.55-3.45 (m, 2 H), 1.30 (t, J = 7.34 Hz,3 H). LCMS RT = 4.32 min, m/z = 420.0 0.019 I-39 Example 4

  N-(4-(1H-pyrazol-1-yl)phenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide ¹H NMR (400 MHz, CHLOROFORM- d) δ ppm 8.36(s, 1 H) 7.90 (s, 1 H) 7.69- 7.77 (m, 3 H) 7.55 (d, J = 8.31 Hz, 2 H)6.90 (t, J = 52.0 Hz, 1 H) 6.48 (s, 1 H) 5.31 (s, 2 H) 3.19 (d, 7 = 7.34Hz, 2 H) 1.46 (t, J = 7.46 Hz, 3 H). LCMS RT = 4.67 min, m/z = 467.00.010 I-40 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3- yl)morpholine-4-sulfonamide ¹H NMR(400 MHz, CD3OD) δ 8.57 (s, 1 H), 8.45 (s, 1 H), 8.27 (m, 1 H), 7.97 (m,1 H), 7.73 (m, 1 H), 7.22 (t, J = 51.6 Hz, 1 H), 4.88 (s, 2 H), 3.36 (m,4 H), 3.10 (m, 4 H) m/z = 459.1 4.22 I-43 Example 3

  (R)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one ¹H NMR (400 MHz,METHANOL-d4) δ = 8.07 (s, 1 H) 7.40 (s, 5 H) 7.19 (t, 1 H, J = 51.6 Hz)5.84 (dd, J = 8.80, 3.67 Hz, 1 H) 5.03 (t, J = 8.80 Hz, 1 H) 4.48 (dd, J= 8.93, 4.03 Hz, 1 H) ppm LCMS: RT = 4.67 min, m/z = 365.1 0.085 I-44Example 3

  (S)-3-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-4-phenyloxazolidin-2-one 1H NMR (400 MHz,METHANOL-d4) δ = 8.07 (s, 1 H), 7.40 (s, 4 H), 7.33-7.38 (m, 1 H), 7.19(t, 1 H, J = 5.6 Hz), 5.84 (dd, J = 8.56, 3.91 Hz, 1 H), 5.03 (t, J =8.93 Hz, 1 H), 4.43-4.51 (m, 1 H) ppm LCMS: RT = 4.95 min, m/z = 365.18.97 I-45 Example 5

  N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CD3OD) δ ppm8.55 (s, 1 H), 8.27-8.24 (m, 2 H), 7.78- 7.67 (m, 2 H), 7.23 (t, J =51.6 Hz, 1 H), 6.15 (s, 2 H), 2.90 (s, 3 H). LCMS RT = 2.431 min, m/z =324.0 1.3 I-46 Example 4

  N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm8.40 (s, 1 H), 7.69 (s, 1 H), 7.49 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H),5.17 (s, 2 H), 3.93 (d, J = 7.2 Hz, 2 H), 3.18 (q, J = 7.6 Hz, 2 H),1.42 (t, J = 7.6 Hz, 3 H), 1.31- 1.22 (m, 1 H), 0.70-0.62 (m, 2 H),0.38-0.32 (m, 2 H). LCMS RT = 2.417 min, m/z = 444.9 0.077 I-47 Example4

  N-(1-cyclopropyl-1H-pyrazol-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.40 (s, 1H), 7.65 (s, 1 H), 7.46 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.14 (s, 2H), 3.58-3.52 (m, 1 H), 3.16 (q, J = 8.0 Hz , 2 H), 1.42 (t, J = 8.0 Hz,3 H), 1.13- 1.00 (m, 4 H). LCMS RT = 1.223 mm, m/z = 430.9 0.070 I-48Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1- (difluoromethyl)-1H-pyrazol-4-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1 H), 7.92(s, 1 H), 7.66 (s, 1 H), 6.96 (t, J = 60.4 Hz, 1 H), 6.84 (t, J = 45.2Hz, 1 H), 5.11 (s, 2 H), 3.10 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.6 Hz,3 H). LCMS RT = 3.543 min, m/z = 441.1 0.262 I-49 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-(2- methoxyethyl)-1H-pyrazol-4-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.40 (s, 1 H), 7.65(s, 1 H), 7.51 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.15 (s, 2 H), 4.22(t, J = 4.8 Hz, 2 H), 3.70 (t, J = 5.2 Hz, 2 H), 3.30 (s, 3 H), 3.17 (q,J = 7.6 Hz, 2 H), 1.41 (t, J = 7.2 Hz, 3 H). LCMS RT = 3.093 min, m/z =448.9 0.134 I-50 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3- yl)cyclopropanesulfonamide 1H NMR(400 MHz, CDCl3) δ ppm 8.69 (d, J = 2.0 Hz, 1 H), 8.53-8.50 (m, 1 H),8.30 (s, 1 H), 7.79-7.76 (m, 1 H), 7.30-7.26 (m, 1 H), 6.83 (t, J = 51.6Hz, 1 H), 5.23 (s, 2 H), 2.53-2.46 (m, 1 H), 1.06-0.95 (m, 4 H). LCMS RT= 2.897 mm, m/z = 414.1 0.036 I-51 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3- yl)methanesulfonamide 1H NMR (400MHz, CDCl3) δ ppm 8.54 (s, 1 H), 8.50 (s, 1 H), 7.93-7.90 (m, 1 H), 7.68(d, J = 8.0 Hz, 1 H), 7.49- 7.44 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1 H),5.84 (s, 2 H), 3.00 (s, 3 H). LCMS RT = 1.096 min, m/z = 387.9 0.676I-52 Example 4

  N-(5-cyanopyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methylethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.96 (d, 1 =2.8 Hz, 1 H), 8.82 (s, 1 H), 8.42 (s, 1 H), 8.18-8.17 (m, 1 H), 6.92 (t,J = 51.6 Hz, 1 H), 5.30 (s, 2 H), 3.21 (q, J = 7.6 Hz, 2 H), 1.44 (t 1 =7.6 Hz, 3H). LCMS RT = 0.752 min, m/z = 427.1 0.022 I-53 Example 4

  N-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm8.70 (d, J = 2.8 Hz, 1 H), 8.40 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H),7.63 (d, J = 8.4 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.29 (s, 2 H),3.22 (q, J = 7.6 Hz, 2 H), 1.75 (s, 6 H), 1.47 (t, J = 7.2 Hz, 3 H).LCMS RT = 0.828 min, m/z = 469.2 0.317 I-54 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluorobenzo[d]oxazol-2-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl₃) δppm 8.45 (s, 1 H), 7.40-7.38 (m, 1 H), 7.10- 6.91 (m, 3 H), 5.40 (s, 2H), 3.29 (q, J = 7.2 Hz, 2 H), 1.52 (t, J = 7.2 Hz, 3 H). LCMS RT =3.800 min, m/z = 460.0 0.104 I-55 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6-fluorobenzo[d]oxazol-2-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δppm 8.44 (s, 1 H), 7.29-7.21 (m, 2 H), 7.10- 7.04 (m, 1 H), 6.91 (t, J =51.6 Hz, 1 H), 5.42 (s, 2 H), 3.29 (q, J = 7.2 Hz, 2 H), 1.52 (t, J =7.2 Hz, 3 H). LCMS RT = 0.863 min, m/z = 459.7 0.124 I-56 Example 4

  N-(6-(difluoromethoxy)pyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm8.39 (s, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H),7.41 (t, J = 51.6 Hz, 1 H), 7.06-6.76 (m, 2 H), 5.24 (s, 2 H), 3.20 (q,J = 7.2 Hz, 2 H), 1.47 (t, J = 7.6 Hz, 3 H). LCMS RT = 0.886 mm, m/z =468.1 0.050 I-57 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1,5-dimethyl-1H-pyrazol-3-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl₃) δ ppm 8.40 (s, 1H), 6.91 (t, J = 51.6 Hz, 1 H), 6.13 (s, 1 H), 5.37 (s, 2 H), 3.70 (s, 3H), 3.27 (q, J = 7.6 Hz, 2 H), 2.24 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).LCMS RT = 3.486 min, m/z = 418.9 0.117 I-58 Example 4

  N-(5-cyclopropylpyridin-3-yl)-N-((5-5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide ¹H NMR (400 MHz, CDCl3) δ ppm 8.45 (s, 1H), 8.41 (s, 1 H), 8.35 (s, 1 H), 7.46 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1H), 5.27 (s, 2 H), 3.19 (q, J = 8.0 Hz, 2 H), 1.92-1.89 (m, 1 H), 1.45(t, J = 7.2 Hz, 3 H), 1.11-1.05 (m, 2 H), 0.76-0.74 (m, 2 H). LCMS RT =0.992 min, m/z = 442.3 0.025 I-59 Example 4

  N-((5-5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5- (trifluoromethyl)pyridin-3-yl)ethanesulfonamide ¹H NMR (400 MHz, CDCl3) δ ppm 8.93 (d, J = 2.0 Hz,1 H), 8.83 (s, 1 H), 8.41 (s, 1 H), 8.10 (s, 1 H), 6.91 (t, J = 51.6 Hz,1 H), 5.31 (s, 2 H), 3.22 (q, J = 7.6 Hz, 2 H), 1.45 (t, J = 7.6 Hz, 3H). LCMS RT = 1.190 mm, m/z = 469.8 0.030 I-60 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5- (difluoromethyl)pyridin-3-yl)ethanesalfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.85 (s, 1 H), 8.73(s, 1 H), 8.40 (s, 1 H), 7.99 (s, 1 H), 6.91 (t, J = 52.0 Hz, 1 H), 6.74(t, J = 56.0 Hz, 1 H), 5.31 (s, 2 H), 3.22 (q, J = 4.0 Hz, 2 H), 1.46(t, J = 8.0 Hz, 3 H). LCMS RT = 2.508 mm, m/z = 452.1 0.070 I-61 Example4

  N-((5-(5-(difluoromethyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6- isopropylpyridin-3-yl)ethanesulfonamide 1HNMR (400 MHz, CDCl3) δ ppm 8.59 (d, J = 2.4 Hz, 1 H), 8.38 (s, 1 H),7.75-7.71 (m, 1 H), 7.22 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 51.6 Hz, 1H), 5.27 (s, 2 H), 3.20 (q, J = 7.2 Hz, 2 H), 3.11-3.03 (m, 1 H), 1.47(t, J = 7.2 Hz, 3 H), 1.29 (d, J = 7.2 Hz, 6 H). LCMS RT = 0.757 mm, m/z= 444.2 0.073 I-62 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6- (difluoromethyl)pyridin-2-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (s, 1 H),7.85-7.69 (m, 2 H), 7.39 (d, J = 7.6 Hz, 1 H), 6.81 (t, J = 51.6 Hz, 1H), 6.47 (t, J = 79.2 Hz, 1 H), 5.54 (s, 2 H), 3.29 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3 H). LCMS RT = 2.238 min, m/z = 452.1 0.0206I-63 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(4,6- dimethylpyrimidin-2-yl)ethanesulfonamide1H NMR (400 MHz, CDCl3) δ ppm 8.40 (s, 1 H), 6.89 (t, J = 51.6 Hz, 1 H),6.77 (s, 1 H), 5.65 (s, 2 H), 3.95 (q, J = 7.6 Hz, 2 H), 2.44 (s, 6 H),1.39 (t, 1 = 7.6 Hz, 3 H). LCMS RT = 3.758 min, m/z = 431.2 0.018 I-64Example 4

  N-((5-(5-(difluoromethyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-ethyl-1H- pyrazol-4-yl)ethanesulfonamide 1HNMR (400 MHz, CDCl3) δ ppm 8.40 (s, 1 H), 7.60 (s, 1 H), 7.49 (s, 1 H),6.91 (t, J = 51.6 Hz, 1 H), 5.16 (s, 2 H), 4.12 (q, J = 7.2 Hz, 2 H),3.17 (q, J = 7.6 Hz, 2 H), 1.50-1.40 (m, 6 H). LCMS RT = 1.418 min, m/z= 418.9 0.065 I-65 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(1-methyl-1H- pyrazol-4-yl)ethanesulfonamide1H NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 7.71 (s, 1 H), 7.48 (s, 1H), 7.11 (t, J = 51.6 Hz, 1 H), 5.10 (s, 2 H), 3.74 (s, 3 H), 3.14 (q, J= 7.2 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 3 H). LCMS RT = 2.950 min, m/z =404.9 0.022 I-66 Example 4

  N-(6-cyanopyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (s, 1H), 8.40 (s, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H),6.91 (t, J = 51.6 Hz, 1 H), 5.35 (s, 2 H), 3.23 (q, J = 7.2 Hz, 2 H),1.43 (t, J = 7.2 Hz, 3 H). LCMS RT = 1.030 mm, m/z = 426.8 0.029 I-67Example 4

  N-(5-cyanopyridin-2-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (s, 1H), 8.39 (s, 1 H), 7.96-7.78 (m, 2 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.63(s, 2 H), 3.48 (q, J = 7.6 Hz, 2 H), 1.43 (t, J = 7.6 Hz, 3 H). LCMS RT= 2.180 min, m/z = 427.1 0.037 I-68 Example 4

  N-((5-(5-(difluoromethyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6-methylpyrazin-2- yl)ethanesulfonamide 1HNMR (400 MHz, CDCl3) δ ppm 8.80 (s, 1 H), 8.39 (s, 1 H), 8.29 (s, 1 H),6.90 (t, J = 51.6 Hz, 1 H), 5.58 (s, 2 H), 3.38 (q, J = 7.2 Hz, 2 H),2.55 (s, 3 H), 1.42 (t, J = 7.6 Hz, 3 H). LCMS RT = 1.657 min, m/z =417.1 0.100 I-69 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(4,6- dimethylpyridin-2-yl)ethanesulfonamide1H NMR (400 MHz, CDCl3) δ ppm 8.38 (s, 1 H), 7.27 (s, 1 H), 7.02-6.72(m, 2 H), 5.58 (s, 2 H), 3.24 (q, J = 7.6 Hz, 2 H), 2.47 (s, 3 H), 2.33(s, 3 H), 1.36 (t, J = 7.4 Hz, 3 H). LCMS RT = 3.082 min, m/z = 429.90.071 I-70 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6- (trifluoromethyl)pyridin-2-yl)ethanesulfonamide 1H NMR (400 MHz, CD3OD) δ ppm 8.42 (s, 1 H),8.07-8.02 (m, 1 H), 7.92- 7.89 (m, 1 H), 7.61-7.58 (m, 1 H), 7.19 (t, J= 51.6 Hz, 1 H), 5.62 (s, 2 H), 3.57 (q, J = 7.2 Hz, 2 H), 1.38 (t, J =7.2 Hz, 3 H). LCMS RT = 2.965 min, m/z = 470.1 0.0281 I-71 Example 8

  2-(2-((3-chlorophenoxy)methyl)thiazol-5-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 1H NMR (400 MHz, CDCl3) δ ppm 8.49(s, 1 H), 7.29-7.24 (m, 1 H), 7.06- 7.04 (m, 2 H), 6.94-6.78 (m, 2 H),5.43 (s, 2 H). LCMS RT = 1.840 min, m/z = 344.1 0.251 I-72 Example 5

  3-chlor-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N- methylaniline 1H NMR (400 MHz,CDCl3) δ ppm 8.55 (s, 1 H), 7.43-6.70 (m, 5 H), 4.93 (s, 2 H), 3.26 (s,3 H). LCMS RT = 3.547 min, m/z = 356.8 0.034 I-73 Example 5

  3-chloro-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)aniline 1H NMR (400 MHz, CDCl3) δ ppm8.37 (s, 1 H), 7.06-6.44 (m, 5 H), 4.66 (s, 3 H). LCMS RT = 2.368 min,m/z = 343.1 0.046 I-74 Example 4

  N-(6-cyclopropylpyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CD3OD) δ ppm 8.46 (d, J =2.4 Hz, 1 H), 8.41 (s, 1 H), 7.80 (dd, J = 8.4, 2.8 Hz, 1 H), 7.33- 7.07(m, 2 H), 5.33 (s, 2 H), 3.31-3.27 (m, 2 H), 2.11-2.08 (m, 1 H), 1.40(t, J = 7.2 Hz, 3 H), 1.04-0.94 (m, 4 H). LCMS RT = 5.273 min, m/z =441.9 0.016 I-75 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyrazin-2- yl)ethanesalfonamide 1H NMR (400MHz, CDCl3) δ ppm 9.00 (s, 1 H), 8.43 (d, J = 2.8 Hz, 1 H), 8.39-8.35(m, 2 H), 6.89 (t, J = 51.6 Hz, 1 H), 5.58 (s, 2 H), 3.41 (q, J = 7.6Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H). LCMS RT = 2.823 mm, m/z = 403.10.023 I-76 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridazin-4- yl)ethanesulfonamide 1H NMR (400MHz, CD3OD) δ ppm 8.57 (d, J = 7.6 Hz, 1 H), 8.53 (s, 1 H), 8.23 (s, 1H), 7.42-7.40 (m, 1 H), 7.22 (t, J = 51.6 Hz, 1 H), 5.85 (s, 2 H), 3.10(q, J = 7.6 Hz, 2 H), 1.36 (t, J = 7.2 Hz, 3H). LCMS RT = 3.671 mm, m/z= 402.9 0.097 I-77 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(2- (trifluoromethyl)pyrimidin-5-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (s, 2 H), 8.43(s, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.32 (d, J = 12 Hz, 2 H) 3.25 (q,J = 7.2 Hz, 2 H), 1.44 (t, J = 7.2 Hz, 3 H). LCMS RT = 2.594 min, m/z =471.1 0.155 I-78 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6- (trifluoromethyl)pyridin-3-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.86 (s, 1 H), 8.40(s, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 6.91 (t,J = 51.6 Hz, 1 H), 5.34 (s, 2 H), 3.23 (q, J = 7.2 Hz, 2 H), 1.45 (t, J= 7.2 Hz, 3 H). LCMS RT = 0.882 min, m/z = 470.1 0.059 I-79 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6-methylpyridin-3- yl)ethanesulfonamide 1HNMR (400 MHz, CDCl3) δ ppm 8.55 (s, 1 H), 8.37 (s, 1 H), 7.73-7.68 (m, 1H), 7.20 (d, J = 7.6 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.27 (s, 2H), 3.20 (q, J = 7.2 Hz, 2 H), 2.56 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).LCMS RT = 0.616 min, m/z = 416.2 0.073 I-80 Example 4

  N-((5-(5-(difluoromethyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-2- yl)ethanesulfonamide 1HNMR (400 MHz, CDCl3) δ ppm 8.37 (s, 1 H), 8.28 (s, 1 H), 7.70-7.60 (m, 1H), 7.50-7.40 (m, 1 H), 6.89 (t, J = 51.6 Hz, 1 H), 5.54 (s, 2 H), 3.25(q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.6 Hz, 3 H). LCMS RT = 2.661 min,m/z = 419.9 0.0265 I-81 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyrimidin- 2-yl)ethanesulfonamide 1HNMR (400 MHz, CDCl3) δ ppm 8.49 (s, 2 H), 8.40 (s, 1 H), 6.90 (t, J =51.6 Hz, 1 H), 5.65 (s, 2 H), 3.91 (q, J = 7.6 Hz, 2 H), 1.45 (t, J =7.6 Hz, 3 H). LCMS RT = 1.977 min, m/z = 421.1 0.116 I-82 Example 9

  N-(3-chloropheny)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol- 2-yl)methyl)propionamide1H NMR (400 MHz, CDCl3) δ ppm 8.28 (s, 1 H), 7.37-7.32 (m, 2 H), 7.25-7.23 (m, 1 H), 7.10-7.07 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.22 (s,2 H), 2.19 (q, J = 7.2 Hz, 2 H), 1.21 (t, J = 7.2 Hz, 3 H). LCMS RT =0.931 min, m/z = 399.1 4.1 I-83 Example 10

  N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.26(s, 1 H), 7.51 (s, 1 H), 7.41-7.30 (m, 3 H), 6.91 (t, 1 = 51.6 Hz, 1 H),5.32 (s, 2 H), 2.59-2.52 (m, 1 H), 1.18- 1.13 (m, 2 H), 1.08-1.04 (m, 2H). LCMS RT = 0.944 min, m/z = 447.1 0.759 I-84 Example 9

  N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanecarboxamide 1H NMR (400 MHz, CDCl3) δ ppm 8.27(s, 1 H), 7.40-7.20 (m, 4 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.25 (s, 2 H),1.50- 1.40 (m, 1 H), 1.18-1.09 (m, 2 H), 0.83-0.74 (m, 2 H). LCMS RT =1.163 min, m/z = 410.8 7.5 I-85 Example 10

  N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesalfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.26 (s, 1H), 7.48 (s, 1 H), 7.37-7.31 (m, 3 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.32(s, 2 H), 3.19 (q, J = 7.2 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H). LCMS RT= 0.922 min, m/z = 435.0 0.584 I-86 Example 10

  N-(3-chlorophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)oxazol-2-yl)methyl)cyclopropanesulfonamide 1H NMR (400 MHz, CDCl3) δ ppm 8.36(s, 1 H), 7.50 (s, 1 H), 7.39-7.37 (m, 1 H), 7.33-7.30 (m, 2 H), 6.91(t, J = 51.6 Hz, 1 H), 5.03 (s, 2 H), 2.69- 2.65 (m, 1 H), 1.09-0.90 (m,4 H). LCMS RT = 3.210 mm, m/z = 431.1 8.0 I-87 Example 4

  N-(2-cyclopropylpyridin-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.42- 8.36 (m, 2H), 7.31 (s, 1 H), 7.18-7.14 (m, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.37(s, 2 H), 3.26 (q, J = 7.6 Hz, 2 H), 2.04- 1.95 (m, 1 H), 1.42 (t, J =7.2 Hz, 3 H), 1.05-1.00 (m, 4 H). LCMS RT = 1.094 min, m/z = 441.9 0.039I-88 Example 4

  N-(6-(difluoromethoxy)pyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)thiazol-2-yl)methyl)cyclopropanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.33 (d, J = 2.8 Hz, 1 H), 7.87 (dd, J = 2.8, 8.8 Hz, 1 H), 7.42 (t,J = 72.0 Hz, 1 H), 7.06-6.77 (m, 2 H), 5.26 (s, 2 H), 2.64-2.48 (m, 1H), 1.21-0.98 (m, 4H). LCMS RT = 0.957 min, m/z = 479.9 0.048 I-89Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5- (trifluoromethyl)pyridin-3-yl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.4 Hz, 1H), 8.87 (d, 4-2.4 Hz, 1 H), 8.44 (s, 1 H), 8.13 (s, 1 H), 6.92 (t, J =51.6 Hz, 1 H), 5.31 (s, 2 H), 3.12 (s, 3 H). LCMS RT = 0.878 min, m/z =455.9 0.049 I-90 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyrazin-2- yl)methanesulfonamide 1H NMR (400MHz, CDCl3) δ 9.00 (s, 1 H), 8.47-8.36 (m, 3 H), 6.91 (t, J = 51.2 Hz, 1H), 5.58 (s, 2 H), 3.27 (s, 3 H). LCMS RT = 0.943 min, m/z = 389.1 0.041I-91 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyrazin-2- yl)cyclopropanesulfonamide 1H NMR(400 MHz, CDCl3) δ 9.02 (d, J = 1.2 Hz, 1 H), 8.46-8.35 (m, 3 H), 6.91(t, J = 51.6 Hz, 1 H), 5.58 (s, 2 H), 2.72-2.61 (m, 1 H), 1.27-1.21 (m,2 H), 1.11-1.01 (m, 2H). LCMS RT = 1.031 min, m/z = 415.1 0.018 I-92Example 4

  N-((5-(5-(difiuoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-3- yl)cyclopropanesalfonamide1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1 H), 8.47 (d, J = 4.0 Hz, 1 H), 8.40(s, 1 H), 7.68-7.62 (m, H), 6.91 (t, J = 51.6 Hz, 1 H), 5.31 (s, 2 H),2.63-2.52 (m, 1 H), 1.17-1.02 (m, 4 H). LCMS RT = 2.295 min, m/z = 431.90.014 I-93 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-methylpyridin-3- yl)methanesulfonamide 1HNMR (400 MHz, CDCl3) δ 8.52- 8.43 (m, 2 H), 8.40 (s, 1 H), 7.65 (s, 1H), 6.91 (t, J = 51.6 Hz, 1 H), 5.27 (s, 2 H), 3.10 (s, 3 H), 2.39 (s, 3H). LCMS RT = 0.828 min, m/z = 401.9 0.055 I-94 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-fluoropyridin-3- yl)methanesulfonamide 1HNMR (400 MHz, CDCl3) δ 8.58 (s, 1 H), 8.49 (s, 1 H), 8.43 (s, 1 H),7.68- 7.65 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.29 (s, 2 H), 3.12 (s,3 H). LCMS RT = 1.877 min, m/z = 406.1 0.025 I-95 Example 4

  N-(5-chloropyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J =2.4 Hz, 1 H), 8.57 (d, J = 2.4 Hz, 1 H), 8.43 (s, 1 H), 7.90 (s, 1 H),6.92 (t, J = 51.6 Hz, 1 H), 5.27 (s, 2 H), 3.11 (s, 3 H). LCMS RT =2.188 min, m/z = 421.8 0.0235 I-96 Example 4

  N-(5-(difluoromethoxy)pyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.63(s, 1 H), 8.46 (s, 1 H), 8.39 (s, 1 H), 7.68 (s, 1 H), 6.91 (t, J = 51.6Hz, 1 H), 6.58 (t, J = 51.6 Hz, 1 H), 5.29 (s, 2 H), 3.22 (q, J = 7.2 Hz, 2 H), 1.44 (t, 1 = 7.6 Hz, 3 H). LCMS RT = 0.907 min, m/z = 467.80.010 I-97 Example 4

  N-(6-cyanopyridin-3-yl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)cyclopropanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J= 2.4 Hz, 1 H), 8.39 (s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.74 (d, J =8.8 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.35 (s, 2 H), 2.59-2.53 (m, 1H), 1.16-1.07 (m, 4 H). LCMS RT = 0.859 min, m/z = 439.0 0.010 I-98Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(2- (trifluoromethyl)pyridin-4-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 5.6 Hz, 1H), 8.39 (s, 1 H), 7.81 (s, 1 H), 7.61-7.53 (m, 1 H), 6.83 (t, J = 51.6Hz, 1 H), 5.35 (s, 2 H), 3.24 (q, J = 7.2 Hz, 2 H), 1.35 (t, J = 7.2 Hz,3 H). LCMS RT = 0.956 min, m/z = 469.9 0.069 I-99 Example 4

  N-(5-chloropyridin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 2.0Hz, 1 H), 8.55 (d, J = 2.0 Hz, 1 H), 8.41 (s, 1 H), 7.89 (t, J = 2.2 Hz,1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.28 (s, 2 H) 3.22 (q, J = 7.2 Hz, 2H), 1.46 (t, 1 = 7.6 Hz, 3 H). LCMS RT = 2.461 min, m/z = 435.9 0.0189I-100 Example 4

  N-((5-(5-(difluoromethyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6- (difluoromethyl)pyridin-3-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 2.4 Hz, 1H), 8.47 (s, 1 H), 8.01 (dd, J = 2.4, 8.4 Hz, 1 H), 7.69 (d, 1 = 8.4 Hz,1 H), 6.91 (t, J = 51.6 Hz, 1 H), 6.63 (t, J = 55.2 Hz, 1 H), 5.32 (s, 2H), 3.21 (q, J = 7.2 Hz, 2 H), 1.45 (t, J = 7.6 Hz, 3 H). LCMS RT =2.547 min, m/z = 452.1 0.065 I-101 Example 3

  1-(5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-5-phenylpyrrolidin-2-one 1H NMR (400 MHz, CDCl3) δ 8.08(s, 1 H), 7.38-7.30 (m, 3 H), 7.18 (d, J = 7.2 Hz, 2 H), 6.88 (t, J =51.6 Hz, 1 H), 5.80 (d, 1 = 7.6 Hz, 1 H), 2.93-2.74 (m, 3 H), 2.25-2.20(m, 1 H). LCMS RT = 2.937 min, m/z = 362.9 0.171 I-102 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(5-(2- hydroxypropan-2-yl)pyridin-2-yl)ethanesalfonamide 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 2.0 Hz, 1H), 8.38 (s, 1 H), 7.86 (d, J = 6.8 Hz, 1 H), 7.60 (d, J = 8.8 Hz, 1 H),6.89 (t, J = 51.6 Hz, 1 H) 5.58 (s, 2 H), 3.29 (q, J = 7.6 Hz , 2 H),1.61 (s, 6 H), 1.39 (t, J = 7.6 Hz, 3 H). LCMS RT = 1.017 min, m/z =459.9 0.137 I-103 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-1-methyl-N-(pyridin-3-yl)cyclopropane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J =2.4 Hz, 1 H), 8.58 (d, J = 3.6 Hz, 1 H), 8.35 (s, 1 H), 7.87-7.81 (m, 1H), 7.38-7.31 (m, I H), 6.90 (t, J = 51.6 Hz, 1 H), 5.35 (s, 2 H), 1.59(s, 3 H), 1.22-1.15 (m, 2 H), 0.79-0.72 (m, 2 H). LCMS RT = 0.956 mm,m/z = 427.9 0.013 I-104 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(6- (methoxymethyl)pyridin-3-yl)ethanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 2.4 Hz, 1H), 8.38 (s, 1 H), 7.83 (dd, J = 2.4, 8.0 Hz, 1 H) 7.48 (d, J = 8.4 Hz,1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.29 (s, 2 H), 4.57 (s, 2 H), 3.49 (s,3 H), 3.20 (q, J = 7.6 Hz, 2 H), 1.46 (t, J = 7.6 Hz, 3 H). LCMS RT =0.789 min, m/z = 446.2 0.051 I-105 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-2-yl)propane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.37(s, 1 H), 8.28 (d, J = 3.2 Hz, 1 H) 7.69- 7.63 (m, 1 H), 7.51-7.43 (m, 1H), 6.89 (t, J = 51.6 Hz, 1 H), 5.52 (s, 2 H), 3.20- 3.14 (m, 2 H),1.91-1.83 (m, 2 H), 1.05 (t, J = 7.6 Hz, 3 H). LCMS Rt = 0.684 min, m/z= 433.9 0.0268 I-106 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thaizol-2-yl}methyl)-N-[6-(2-hydroxyropan-2-yl)pyridin-3-yl]ethane-1- sulfonamide ¹H NMR (400 MHz,CDCl₃) δ 8.55 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.60(d, J = 8.4 Hz, 1 H), 6.89 (t, J = 52.0 Hz, 1 H), 5.58 (s, 2 H), 3.30(q, J = 7.2 Hz, 2 H), 2.63 (s, 1 H), 1.39 (t, J = 7.6 Hz, 3 H),1.30-1.23 co 6 H), LCMS R_(T) = 1.467 min, m/z = 460.2 0.480 I-107Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methoxy-N-(pyridin-3-yl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 8.57 (d, J = 3.6 Hz, 1 H), 8.34 (s, 1 H), 7.91-7.88 (m, 1 H),7.36-7.33 (m, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.24 (s, 2 H), 3.87 (t,J = 5.2 Hz, 2 H), 3.51 (s, 3 H), 3.35 (t, J = 5.2 Hz, 2 H). LCMS R_(T) =1.284 min, m/z = 431.9 0.0212 I-108 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(5-ethoxypyridin-3-yl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.40(s, 1 H), 8.32-8.27 (m, 2 H), 7.42-7.38 (m, 1 H), 6.92 (t, J = 51.6 Hz,1 H), 5.31 (s, 2 H), 4.10 (q, J = 6.8 Hz, 2 H), 3.22 (q, J = 7.2 Hz, 2H), 1.49-1.43 (m, 6 H). LCMS R_(T) = 0.604 min, m/z = 446.0 0.0138 I-109Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.60(d, J = 2.0 Hz, 1 H), 8.54 (s, 1 H), 8.40 (s, 1 H), 7.88 (t, J = 2.4 Hz,1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.27 (s, 2 H), 3.22-3.00 (m, 2 H),1.99-1.70 (m, 2 H), 1.09 (t, J = 7.6 Hz, 3 H). LCMS R_(T) = 0.668 min,m/z = 449.9 0.00392 I-110 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)propane-]-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.56(s, 1 H), 8.46 (d, J = 2.4 Hz, 1 H), 8.40 (s, 1 H), 7.67-7.61 (m, 1 H),6.91 (t, J = 51.6 Hz, 1 H) 5.29 (s, 2 H), 3.19-3.09 (m, 2 H), 1.97-1.85(m, 2 H), 1.08 (t, J = 7.2 Hz, 3 H). LCMS R_(T) = 2.144 min, m/z = 434.20.0104 I-111 Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.98(d, J = 2.4 Hz, 1 H), 8.84 (s, 1 H), 8.45 (s, 1 H), 8.20 (s, 1 H), 6.93(t, J = 51.2 Hz, 1 H), 5.29 (s, H), 3.11 (s, 3 H). LCMS R_(T) = 1.456min, m/z = 412.8 0.0374 I-112 Example 4

  N-[5-(1,1-difluorethyl)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.79(s, 1 H), 8.72 (s, 1 H), 8.40 (s, 1 H), 7.96 (s, 1 H) 6.91 (t, J = 52.0Hz, 1 H), 5.30 (s, 2 H), 3.21 (q, J = 7.2 Hz, 2 H), 1.97 (t, J = 18.4Hz, 3 H), 1.46 (t, J = 7.6 Hz, 3 H). LCMS R_(T) = 1.138 min, m/z = 466.20.0101 I-113 Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.95(d, J = 2.4 Hz, 1 H), 8.82 (d, J = 2.0 Hz, 1 H), 8.42 (s, 1 H),8.20-8.12 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.29 (s, 2 H), 3.19-3.08 (m, 2 H), 1,98-1.85 (m, 2 H), 1.09 (t, J = 7.6 Hz, 3 H). LCMS R_(T)= 1.560 min, m/z = 441.2. 0.0429 I-114 Example 4

  N-phenyl-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2- yl}methyl)methanesulfonamide 1H NMR (400MHz, CDCl₃) δ 8.39 (s, 1 H), 7.48-7.38 (m, 5 H), 5.28 (s, 2 H), 3.06 (s,3 H). LCMS R_(T) = 2.568 min, m/z = 404.8 0.354 I-115 Example 4

  N-(5-fluoropyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.57(s, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 8.42 (s, 1 H), 7.68-7.63 (m, 1 H),5.31 (s, 2 H), 3.22 (q, J = 7.2 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H).LCMS R_(T) = 0.904 min, m/z = 437.9 0.022 I-116 Example 4

  N-[6-(1,1-difluoroethyl)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.74(d, J = 2.4 Hz, 1 H), 8.39 (s, 1 H), 7.98-7.92 (m, 1 H), 7.70 (d, J =8.4 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.32 (s, 2 H), 3.22 (q, J =7.6 Hz, 2 H), 2.01 (t, J = 18.8 Hz, 3 H), 1.46 (t, J = 7.6 Hz, 3 H).LCMS R_(T) = 0.908 min, m/z = 465.9 0.0514 I-117 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.61(d, J = 2.4 Hz, 1 H), 8.55 (d, J = 2.4 Hz, 1 H), 8.42 (s, 1 H), 7.88 (t,J = 2.0 Hz, 1 H), 5.29 (s, 2 H), 3.21 (q, J = 4.0 Hz, 2 H), 1.46 (t, J =8.0 Hz, 3H). LCMS R_(T) = 2.591 min, m/z = 453.8 0.0245 I-118 Example 4

  N-(pyrazin-2-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2- yl}methyl)ethane-1-sulfonamide ¹HNMR (400 MHz, CDCl₃) δ 9.00 (s, 1 H) 8.44-8.37 (m, 3 H), 5.58 (s, 2 H),3.41 (d, J = 6.8 Hz, 2 H), 1.43 (t, J = 6.8 Hz, 3 H). LCMS R_(T) = 0.895min, m/z = 420.9 0.0278 I-119 Example 4

  N-(pyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2- yl}methyl)ethane-1-sulfonamide ¹HNMR (400 MHz, CDCl₃) δ 8.73 (s, 1 H), 8.62-8.60 (m, 1 H), 8.41 (s, 1 H),7.86 (d, J = 8.0 Hz, 1 H), 7.40-7.35 (m, 1 H), 5.32 (s, 2 H), 3.22 (q, J= 6.8 Hz, 2 H), 1.48 (t, J = 7.2 Hz, 3H). LCMS R_(T) = 1.897 min, m/z =420.1 0.042 I-120 Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.98(d, J = 2.8 Hz, 1 H), 8.85 (s, 1 H), 8.46 (s, 1 H), 8.20 (t, J = 2.0 Hz,1 H) 5.30 (s, 2 H), 3.11 (s, 3 H). LCMS R_(T) = 2.105 min, m/z = 431.10.111 I-121 Example 4

  N-(3-fluorophenyl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.40(s, 1 H), 7.41-7.36 (m, 1 H), 7.28 (s, 1 H), 7.25-7.22 (m, 1 H),7.09-7.04 (m, 1 H) 5.30 (s, 2 H), 3.19 (q, J = 7.6 Hz, 2 H) 1.45 (t, J =7.2 Hz, 3 H). LCMS R_(T) = 1.978 min, m/z = 437.1 0.0839 I-122 Example 4

  N-phenyl-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2- yl}methyl)ethane-1-sulfonamide ¹H NMR(400 MHz, CDCl₃) δ 8.38 (s, 1 H), 7.50-7.30 (m, 5 H), 5.31 (s, 2 H),3.17 (q, J = 7.2 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H). LCMS R_(T) = 0.973min, m/z = 419.0 0.0249 I-123 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1-methyl-1H-pyrazol-4-yl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1 H),7.57 (s, 1 H), 7.48 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.14 (s, 2 H),3.88 (s, 3 H), 3.03 (s, 3 H). LCMS R_(T) = 1.057 min, m/z = 390.9 0.0388I-124 Example 5

  5-[({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2- yl]-1,3-thiazol-2-yl}methyl(methyl)amino]pyridine-3- carbonitrile 1H NMR (400 MHz, CDCl₃)δ 8.46 (s, 1 H), 8.41 (s, 1 H), 8.33 (s, 1 H), 7.25 (s, 1 H) 6.90 (t, J= 51.6 Hz, 1 H), 4.92 (s, 2 H), 3.27 (s, 3 H). LCMS R_(T) = 0.971 min,m/z = 349.0 0.0636 I-125 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(pyridin-3- yl)propane-1-sulfonamide ¹HNMR (400 MHz, CDCl₃) δ 8.71 (d, J = 2.4 Hz, 1 H), 8.60-8.56 (m, 1 H),8.38 (s, 1 H), 7.85-7.82 (m, 1 H), 7.39- 7.32 (m, 1 H), 6.91 (t, J =51.6 Hz, 1 H), 5.29 (s, 2 H), 3.18-3.11 (m, 2 H), 1.98-1.89 (m, 2 H),1.09 (t, J = 7.2 Hz. 3H). LCMS R_(T) = 0.776 min, m/z = 416.1 0.0599I-126 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-{1-[2-(trifluoromethoxy)ethyl]-1H-pyrazol-4- yl}ethane-1-sulfonamide ¹H NMR(400 MHz, CDCl₃) δ 8.39 (s, 1 H), 7.64 (s, 1 H), 7.57 (s, 1 H), 6.91 (t,J = 51.6 Hz, 1 H), 5.16 (s, 2 H) 4.36- 4.33 (m, 2 H), 4.30-4.23 (m, 2H), 3.15 (q, J = 7.6 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H). LCMS R_(T) =1.043 min, m/z = 502.9 0.134 I-127 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- fluoropyridin-2-yl)methanesulfonamide¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1 H), 8.29 (d, J = 3.2 Hz, 1 H),7.67-7.61 (m, 1 H), 7.53-7.46 (m, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.50(s, 2 H), 3.10 (s, 3 H). LCMS R_(T) = 0.854 min, m/z = 406.1 0.0215I-128 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1,1-difluoro-N- (1-propyl-1H-pyrazol-4-yl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1 H), 7.49 (d,J = 4.4 Hz, 2 H), 6.92. (t, J = 51.6 Hz, 1 H) 6.44 (t, J = 53.2 Hz, 1H), 5.21 (s, 2 H), 4.02 (t, J = 7.2 Hz, 2 H), 1.94-1.78 (m, 2 H) 0.88(t, 7 = 7.6 Hz, 3H). LCMS R_(T) = 0.901 min, m/z = 455.1 0.2.51 I-129Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1-propyl-1H-pyrazol-4-yl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1 H),7.58 (s, 1 H), 7.49 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.14 (s, 2 H),4.03 (1, J = 7.2 Hz, 2 H), 3.03 (s, 3 H), 1.92-1.81 (m, 2 H), 0.90 (t, J= 7.2 Hz, 3 H). LCMS R_(T) = 0.795 min, m/z = 418.9 0.118 I-130 Example4

  N-({5-[5-(difluoroinethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1-methyl-1H-pyrazol-4-yl)cyclopropanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s,1 H), 7.56 (s, 1 H), 7.52 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.15 (s,2 H), 3.87 (s, 3 H), 2.58-2.50 (m, 1 H), 1.20-1.15 (m, 2 H), 1.07-1.01(m, 2H). LCMS R_(T) = 1.320 min, m/z = 416.8 0.0348 I-131 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.50(d, J = 2.4 Hz, 1 H), 8.41 (s, 1 H), 8.38 (s, 1 H), 7.65 (s, 1 H), 6.91(t, J = 51.6 Hz, 1 H), 5.29 (s, 2 H), 3.20 (q, J = 7.6 Hz, 2 H), 2.37(s, 3 H), 1.47 (t, J = 7.6 Hz, 3 H). LCMS R_(T) = 0.714 min, m/z = 416.20.013 I-132 Example 4

  N-[5-(2,2-difluoroethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.40(s, 2 H), 8.32 (d, J = 2.4 Hz, 1 H), 7.45 (t, J = 2.4 Hz, 1 H), 6.91 (t,J = 51.6 Hz, 1 H), 6.25-5.96 (m, 1 H), 5.30 (s, 2 H), 4.30- 4.20 (m, 2H), 3.21 (q, J = 7.2 Hz, 2 H), 1.46 (t, J = 7.6 Hz, 3 H). LCMS R_(T) =0.857 min, m/z = 482.2 0.00964 I-133 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl-1,1-difluoro-N-(5-fluoropyridin-2-yl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.39(s, 1 H), 8.30 (d, J = 2.8 Hz, 1 H), 7.58-7.55 (m, 1 H), 7.54-7.48 (m, 1H), 7.03 (t, J = 51.6 Hz, 1 H), 6.33 (t, J 53.6 Hz, 1 H), 5.55 (s, 2 H).LCMS R_(T) = 0.954 min, m/z = 441.9 0.0857 I-134 Example 4

  N-[1-(1-cyano-1-methylethyl)-1H-pyrazol-4-yl]-N-({5-[5-(difluoromethyl)-1,3,4- oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1 H),7.83 (s, 1 H), 7.63 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.17 (s, 2 H),3.17 (q, J = 7.2 Hz, 2 H), 1.99 (s, 6 H), 1.42 (t, J = 7.2 Hz, 3 H).LCMS R_(T) = 1.012 min, m/z = 458.1 0.121 I-135 Example 5

  3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N- ethylaniline ¹H NMR (400MHz, CDCl₃) δ 8.45 (s, 1 H), 7.14 (t, J = 8.0 Hz, 1 H), 6.88 (t, J =51.6 Hz, 1 H), 6.76-6.74 (m, 2 H), 6.64- 6.60 (m, 1 H), 4.79 (s, 2 H),3.58 (q, J = 7.2 Hz, 2 H), 1.30 (t, J = 7.2 Hz, 3 H). LCMS R_(T) = 1.098min, m/z = 370.9 0.0531 I-136 Example 4

  N-(5-cyclopropylpyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.46(s, 1 H), 8.41 (s, 1 H), 8.37 (s, 1 H), 7.46 (s, 1 H), 6.91 (t, J = 51.6Hz, 1 H), 5.25 (s, 2 H), 3.09 (s, 3 H), 1.96-1.89 (m, 1 H), 1.14-1.06(m, 2 H), 0.79-0.71 (m, 2 H). LCMS R_(T) = 0.743 min, m/z = 427.9 0.013I-137 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[6- (difluoromethyl)pyridin-2-yl]methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1 H), 7.90 (t,J = 8.0 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H),6.89 (t, J = 51.6 Hz, 1 H), 6.54 (t, J = 55.2 Hz, 1 H), 5.59 (s, 2 H),3.23 (s, 3 H). LCMS R_(T) = 0.899 min, m/z = 437.9 0.0107 I-138 Example4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl-N-[l-(propan-2-yl)-1H-pyrazol-4-yl]ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.37(s, 1 H), 7.57 (s, 1 H), 7.46 (s, 1 H), 6.87 (t, J = 51.2 Hz, 1 H), 5.12(s, 2 H), 4.44- 4.34 (m, 1 H), 3.13 (q, J = 7.2 Hz, 2 H), 1.45 (d, J =6.8 Hz, 6 H), 1.39 (t, J = 7.2 Hz, 3 H). LCMS R_(T) = 1.141 min, m/z =433.2 0.043 I-139 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[l-(propan-2-yl)-1H-pyrazol-4-yl]methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.39(s, 1 H), 7.58 (s, 1 H), 7.46 (s, 1 H), 6.88 (t, J = 51.6 Hz, 1 H), 5.11(s, 2 H), 4.45- 4.35 (m, 1 H), 3.00 (s, 3 H), 1.46 (d, J = 6.8 Hz, 6 H).LCMS R_(T) = 0.997 min, m/z = 419.2 0.118 I-140 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[6- (trifluoromethyl)pyridin-2-yl]methanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1 H), 7.95-7.85(m, 2 H), 7.51 (d, J = 7.2 Hz, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.61(s, 2 H), 3.29 (s, 3 H). LCMS R_(T) = 1.112 min, m/z = 455.8 0.0576I-141 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1,1-difluoro-N-(pyridin-3-yl)methanesulfonamide ¹H NMR (400 MHZ, CDCl₃) δ 8.70- 8.60(m, 2 H), 8.39 (s, 1 H), 7.75 (d, J = 6.8 Hz, 1 H), 7.39-7.36 (m, 1 H),6.92 (t, J = 51.6 Hz, 1 H), 6.49 (t, J = 53.2 Hz, 1 H), 5.35 (s, 2 H).LCMS R_(T) = 0.965 min, m/z = 423.8 0.0655 I-142 Example 5

  3-chloro-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N- (2-methoxyethyl)aniline ¹HNMR (400 MHz, CDCl₃) δ 8.44 (s, 1 H), 7.13 (t, J = 8.0 Hz, 1 H), 6.88(t, J = 89.2 Hz, 1 H), 6.80-6.70 (m, 2 H), 6.68- 6.55 (m, 1H), 4.94 (s,2 H), 3.74-3.71 (m, 2 H), 3.70-3.65 (m, 2 H), 3.38 (s, 3 H). LCMS R_(T)= 1.055 min, m/z = 400.9 0.0245 I-143 Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)cyclopropanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ8.99 (d, J = 2.0 Hz, 1 H), 8.83 (s, 1 H), 8.41 (s, 1 H), 8.18 (t, J =2.0 Hz, 1 H), 6.92 (t, J = 51.6 Hz, 1H), 5.31 (s, 2 H), 2.59-2.50 (m, 1H), 1.13-1.08 (m, 4 H). LCMS R_(T) = 0.834 min, m/z = 439.1 0.0153 I-144Example 11

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s,1 H), 7.38 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.11 (s, 2 H), 3.76 (s,3 H), 3.20 (q, J = 7.2 Hz, 2 H), 2.25 (s, 3 H), 1.47 (t, J = 7.4 Hz, 3H). LCMS R_(T) = 0.751 min, m/z = 419.0 0.102 I-145 Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-2-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.61(d, J = 2.0 Hz, 1 H), 8.45 (d, 1 = 2.4 Hz, 1 H), 8.38 (s, 1 H), 7.68 (t,J = 2.0 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 6.58 (t, J = 72.0 Hz, 1H), 5.31 (s, 2 H), 3.40-3.29 (m, 1 H), 1.45 (d, J = 6.8 Hz, 6 H). LCMSRT = 1.625 min, m/z = 482.2. 0.0102 I-146 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(5-ethylpyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CD3OD) δ 8.59(s, 1 H), 8.40 (s, 2 H), 8.02 (s, 1 H), 7.19 (t, J = 51.2 Hz, 1 H), 5.40(s, 2 H), 3.40- 3.30 (m, 2 H), 2.73 (q, J = 7.6 Hz, 2 H) 1.39 (t, J =7.6 Hz, 3 H), 1.25 (t, J = 7.6 Hz, 3 H). LCMS RT = 1.215 min, m/z =430.2 0.0162 I-147 Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.62(s, 1 H), 8.49 (s, 1 H), 8.43 (s, 1 H), 7.69 (s, 1 H), 6.92 (t, J = 51.6Hz, 1 H), 6.59 (t, J = 72.0 Hz, 1 H), 5.28 (s, 2 H), 3.12 (s, 3 H). LCMSRT = 1.512 min, m/z = 453.8 0.019 I-148 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methoxypyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ ppm8.39 (s, 1 H), 8.30-8.28 (m, 2 H), 7.38 (s, 1 H), 6.91 (t, J = 51.6 Hz,1 H), 5.30 (s, 2 H), 3.87 (s, 3 H), 3.21 (q, J = 7.6 Hz, 2 H), 1.46 (t,J = 7.6 Hz, 3 H). LCMS RT = 1.360 min, m/z = 431.9 [M + H]+ 0.0192 I-149Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-2-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.95(d, J = 2.8 Hz, 1 H), 8.80 (s, 1 H), 8.39 (s, 1 H), 8.16 (s, 1 H), 6.92(t, J = 51.6 Hz, 1 H), 5.30 (s, 2 H), 3.39-3.25 (m, 1 H), 1.45 (d, J =6.8 Hz, 6 H). LCMS RT = 1.584 min, m/z = 440.9 0.0231 I-150 Example 4

  N-[5-(1,1-difluorethyl)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.80(s, 1 H), 8.75 (s, 1 H), 8.43 (s, 1 H), 7.98 (s, 1 H), 6.92 (t, J = 51.6Hz, 1 H), 5.29 (s, 2 H), 3.12 (s, 3 H), 1.98 (t, J = 18.0 Hz, 3 H). LCMSRT = 1.554 mm, m/z = 451.8 0.0255 I-151 Example 4

  N-(5-chloropyridin-2-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.37(d, J = 4.0 Hz, 2 H), 7.74-7.67 (m, 2 H), 6.90 (t, J = 51.6 Hz, 1 H),5.56 (s, 2 H), 3.29 (q, J = 7.2 Hz, 2 H), 1.39 (t, 1 = 7.2 Hz, 3 H).LCMS RT = 1.826 min, m/z = 436.1 0.0315 I-152 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-[5-(propan-2-yloxy)pyridin-3-yl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.39(s, 1 H), 8.25 (s, 2 H), 7.35 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.29(s, 2 H), 4.61- 4.55 (m, 1 H), 3.25-3.18 (m, 2 H), 1.61 (s, 3 H), 1.36(d, J = 4.4 Hz, 6 H). LCMS RT = 1.666 min, m/z = 459.9 0.0429 I-153Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-2-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.22(s, 1 H), 8.10 (s, 1 H), 7.40 (s, 2 H), 6.75 (t, J = 51.6 Hz, 1 H), 5.42(s, 2 H), 3.09 (q, J = 7.6 Hz, 2 H), 2.18 (s, 3 H), 1.23 (t, J = 7.2 Hz,3 H). LCMS RT = 1.666 mm, m/z = 416.2 0.043 I-155 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(4-methylpyridin-2-yl)ethane-l-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.39(s, 1 H), 8.29 (d, J = 4.8 Hz, 1 H), 7.47 (s, 1 H), 7.01 (d, J = 4.8 Hz,1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.60 (s, 2 H), 3.28 (q, J = 7.6 Hz, 2H), 2.40 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H). LCMS RT = 1.635 min m/z =416.2 0.0528 I-156 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-(morpholin-4- yl)ethane-1-sulfonamide 1H NMR (400MHz, CD3OD) δ ppm 8.68 (d, J = 2.4 Hz, 1 H), 8.52 (d, J = 2.0 Hz, 1 H),8.44 (s, 1 H), 8.17 (t, J = 2.0 Hz, 1 H), 7.22 (t, J = 52.0 Hz, 1 H),5.45 (s, 2 H), 3.73-3.70 (m, 4 H), 3.58 (t, J = 7.6 Hz, 2 H), 2.89 (t, J= 6.8 Hz, 2 H) 2.58-2.51 (m, 4 H). LCMS RT = 0.992 min, m/z = 521.20.00253 I-157 Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methylpropane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.59 (d, J = 2.0 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.40 (s,1 H), 7.67 (t, J = 2.4 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 6.59 (t, J= 72.0 Hz, 1 H), 5.28 (s, 2 H), 3.05 (d, J = 8.0 Hz, 2 H), 2.40-2.30 (m,1 H), 1.12 (d, J = 6.8 Hz, 6 H). LCMS RT = 0.644 min, m/z = 496.10.00693 I-158 Example 4

  N-(5-chloropyridin-3-yl)-2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ ppm8.63 (d, J = 2.4 Hz, 1 H), 8.60 (d, J = 2.0 Hz, 1 H), 8.46 (s, 1 H),7.91 (t, J = 2.4 Hz, 1 H), 6.93 (T, J = 51.6 Hz, 1 H), 5.30 (s, 2 H),3.54 (t, J = 7.2 Hz, 2 H), 2.98 (t, J = 7.2 Hz, 2 H). LCMS RT = 0.576min, m/z = 461.1 0.00722 I-159 Example 4

  N-[5-(1,1-difluoroethyl)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methoxyethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.85 (s, 1 H), 8.56 (s, 1 H), 8.72 (s, 1 H), 8.35 (s, 1 H),8.01 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.26 (s, 2 H), 3.87 (t, J =5.2 Hz, 2 H), 3.50 (s, 3 H), 3.36 (t, J = 5.2 Hz, 2 H), 1.97 (t, J =18.4 Hz, 3 H). LCMS RT = 1.701 min, m/z = 495.9 0.00994 I-160 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.49(d, J = 2.4 Hz, 1 H), 8.41 (s, 1 H), 8.38 (s, 1 H), 7.65 (s, 1 H), 6.91(t, J = 51.6 Hz, 1 H), 5.27 (s, 2 H), 3.16-3.08 (m, 2 H), 2.37 (s, 3 H),1.99-1.85 (m, 2 H), 1.09 (t, J = 7.2 Hz, 3 H). LCMS RT = 1.815 min, m/z= 430.2 0.0109 I-161 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methoxyethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.67 (s, 1 H), 8.53 (s, 1 H), 8.35 (s, 1 H), 7.90 (t, J = 2.0Hz, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.22 (s, 2 H), 3.86 (t, J = 5.6Hz, 2 H) 3.49 (s, 3 H), 3.36 (t, J = 5.6 Hz, 2 H). LCMS RT = 1.529 min,m/z = 466.1 0.012 I-162 Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.60(s, 1 H), 8.47 (s, 1 H), 8.40 (s, 1 H), 7.67 (s, 1 H), 6.91 (t, J = 51.6Hz, 1 H), 6.59 (t, J = 72.0 Hz, 1 H), 5.29 (s, 2 H) 3.19- 3.11 (m, 2 H),1.99-1.86 (m, 2 H), 1.09 (t, J = 7.2 Hz, 3 H). LCMS RT = 1.794 min, m/z= 481.9 0.0144 I-163 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methyl-N-(pyridin-3-yl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J= 2.4 Hz, 1 H), 8.60-8.55 (m, 1 H), 8.41 (s, 1 H), 8.07-8.01 (m, 1 H),7.53- 7.47 (m, 1 H), 7.20 (t, J = 51.6 Hz, 1 H), 5.37 (s, 2 H), 3.20 (d,J = 6.4 Hz, 2 H), 2.34-2.22 (m, 1 H), 1.10 (d, J = 6.4 Hz, 6 H). LCMS RT= 1.423 min, m/z = 430.2 0.0161 I-164 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-(morpholin-4-yl)-N-(pyridin-3-ylethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ ppm8.73 (d, J = 2.4 Hz, 1 H), 8.60-8.55 (m, 1 H), 8.38 (s, 1 H), 7.87-7.81(m, 1 H), 7.38-7.33 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.32 (s, 2 H),3.76-3.72 (m, 4 H), 3.37 (t, J = 7.2 Hz, 2 H), 2.90 (t, J = 6.8 Hz, 2H), 2.52-2.50 (m, 4 H). LCMS RT = 0.430 min, m/z = 487.2 0.0173 I-165Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methoxyethane-1- sulfonamide 1H NMR (400 MHz,CD3OD) δ 8.59 (s, 1 H), 8.40 (s, 2 H), 7.87 (d, J = 2.4 Hz, 1 H), 7.19(t, J = 51.6 Hz, 1 H), 6.97 (t, J = 72.8 Hz, 1 H), 5.34 (s, 2 H), 3.83(t, J = 5.2 Hz, 2 H), 3.52 (t, 1 = 5.6 Hz, 2 H). 3.30 (t, J = 1.6 Hz, 3H). LCMS RT = 1.533 mm, m/z = 498.2 0.0196 I-166 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methoxy-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CD3OD) δ 8.49(s, 1 H), 8.39 (s, 1 H), 8.34 (s, 1 H), 7.87 (s, 1 H), 7.20 (t, J = 51.6Hz, 1 H), 5.31 (s, 2 H), 3.83 (t, J = 5.2 Hz, 2 H), 3.49 (t, 1 = 5.6 Hz,2 H), 3.43 (s, 3 H), 2.38 (s, 3 H). LCMS RT = 2.329 min, m/z = 446.50.0266 I-167 Example 4

  N-(5-chloropyridin-2-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ8.40- 8.35 (m, 2 H), 7.73-7.68 (m, 1 H), 7.66- 7.60 (m, 1 H), 6.89 (t, J= 51.6 Hz, 1 H), 5.55 (s, 2 H), 3.26-3.17 (m, 2 H), 1.93-1.81 (m, 2 H),1.05 (t, J = 7.4 Hz. 3H). LCMS RT = 2.072 min, m/z = 449.8 0.0266 I-168Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-methylpropane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.95 (d, J = 2.4 Hz, 1 H), 8.82 (s, 1 H), 8.42 (s, 1 H), 8.16(s, 1 H), 6.92 (t, J = 52.0 Hz, 1 H) 5.28 (s, 2 H), 3.03 (d, J = 6.4 Hz,2 H), 2.42-2.28 (m, 1 H), 1.12 (d, J = 6.8 Hz, 6 H). LCMS RT = 1.690min, m/z = 455.2 0.0305 I-169 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(6-methylpyridin-2-yl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.38(s, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H),7.02-6.75 (m, 2 H), 5.59 (s, 2 H), 3.22-3.15 (m, 2 H), 2.52 (s, 3 H),1.93-1.80 (m, 2 H), 1.03 (t, J = 7.6 Hz, 3 H). LCMS RT = 1.942 min, m/z= 429.9 0.0309 I-170 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(pyridin-3- yl)butane-1-sulfonamide 1HNMR (400 MHz, CDCl3) δ 8.70 (s, 1 H), 8.58 (d, J = 4.8 Hz, 1 H), 8.38(s, 1 H), 7.90-7.80 (m, 1 H), 7.45-7.31 (m, 1 H), 6.91 (t, J = 51.2 Hz,1 H), 5.29 (s, 2 H), 3.21-3.06 (m, 2 H), 1.92-1.83 (m, 2 H), 1.52-1.43(m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H). LCMS RT = 0.623 min, m/z = 429.90.0264 I-171 Example 2

  l-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1,2,3,4- tetrahydro-1,7-naphtbyridin-2-one1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H), 8.42 (s, 1 H), 8.31 (d, J = 3.6Hz, 1 H), 7.16 (d, J = 4.4 Hz, 1 H), 6.89 (t, J = 51.6 Hz, 1 H), 5.52(s, 2 H), 3.04 (t, J = 6.8 Hz, 2 H), 2.81 (t, J = 8.0 Hz, 2 H). LCMS RT= 1.398 min, m/z = 363.9 0.0215 I-172 Example 2

  4-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2H,3H,4H- pyrido[4,3-b][1,4]oxazin-3-one 1HNMR (400 MHz, CDCl3) δ 8.52 (s, 1 H), 8.43 (s, 1 H), 8.27 (d, J = 5.6Hz, 1 H), 6.96 (d, 1 = 5.2 Hz, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.52(s, 2 H), 4.85 (s, 2 H). LCMS RT = 0.418 min, m/z = 366.0 0.025 I-173Example 2

  4-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 8.01-8.05 (m, 1H), 7.29 (dd, J = 8.1, 1.5 Hz, 1 H), 7.01 (dd, J =8.1, 1.5 Hz, 1H), 6.89 (t, J = 51.6 Hz, 1 H), 5.70 (s, 2 H) LCMS: RT =5.00 min, m/z = 394.0 0.108 I-174 Example 4

  N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methyl)-N-(pyridin-3-yl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)- yl)ethane-1-sulfonamide 1H NMR(400 MHz, CDCl3) δ 8.76 (s, 1 H), 8.58 (d, J = 4.4 Hz, 1 H), 8.39 (s, 1H), 7.89 (d, J = 8.4 Hz, 1 H), 7.40-7.35 (m, 1 H), 6.91 (t, J = 51.6 Hz,1 H), 5.33 (s, 2 H), 3.75-3.70 (m, 4 H), 3.49 (t, J = 6.8 Hz, 2 H), 3.07(t, 1 = 6.8 Hz, 2 H), 2.99-2.96 (m, 4 H), 2.49 (d, J = 6.0 Hz. 2H). LCMSRT = 1.435 min, m/z = 513.0 0.022 I-175 Example 6

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- fluoropyridin-3-yl)-3-(morpholin-4-yl)propanamide 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 2.0 Hz, 1 H),8.43-8.36 (m, 2 H), 7.50-7.44 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.20(s, 2 H), 3.71-3.66 (m, 4 H), 2.81 (t, J = 6.8 Hz, 2 H), 2.50-2.22 (m, 6H). LCMS RT = 0.400 min, m/z = 469.2 0.496 I-176 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H,2H,3H- pyrido[3,4-b][1,4]oxazin-2-one 1HNMR (400 MHz, CD3OD) δ 8.54- 8.53 (m, 1 H), 8.13-8.10 (m, 1 H), 7.22 (t,J = 51.6 Hz, 1 H), 6.97-6.89 (m, 1 H), 5.84-5.78 (m, 1 H), 4.72-4.45 (m,4 H). LCMS RT = 1.091 min, m/z = 365.8 2.52 I-177 Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)butane-2-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.59(d, J = 2.0 Hz, 1 H), 8.45 (d, J = 2.4 Hz, 1 H), 8.37 (s, 1 H), 7.67 (t,J = 2.4 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 6.58 (t, J = 72.0 Hz, 1H), 5.38-5.20 (m, 2 H), 3.15- 3.07 (m, 1 H), 2.13-2.02 (m, 1 H),1.73-1.60 (m, I H), 1.43 (d, J = 6.8 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3 H).LCMS RT = 1.580 min, m/z = 496.2 0.006 I-178 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[(pyridin-3-yl)methyl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.62- 8.55 (m,2 H), 8.42 (s, 1 H), 7.88-7.82 (m, 1 H), 7.38-7.34 (m, 1 H), 6.88 (t, J= 51.6 Hz, 1 H), 4.71 (s, 2 H), 4.60 (s, 2 H), 3.19 (q, J = 7.6 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3 H). LCMS RT = 1.031 min, m/z = 416 2 4.35I-179 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}-N-(pyridin-3- yl)ethane-1-sulfonamide 1HNMR (400 MHz, CDCl3) δ 8.76 (d, J = 2.4 Hz, 1 H), 8.58 (d, 1 = 3.2 Hz, 1H), 8.38 (s, 1 H), 7.89-7.86 (m, 1 H), 7.39-7.35 (m, 1 H), 6.91 (t, J =51.6 Hz, 1 H), 5.34 (s, 2 H), 4.22 (d, J = 11.2 Hz, 2 H), 3.81 (d, J =11.6 Hz, 2 H), 3.64 (d, 1 = 6.4 Hz, 2 H), 3.36-3.20 (m, 4 H), 2.74-2.69(m, 1 H), 1.91 (d, J = 8.8 Hz, 1 H). LCMS RT = 1.438 min, m/z = 499.00.013 I-180 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- fluoropyridin-3-yl)-2-{hexahydro-1H-furo[3,4-c]pyrrol-5-yl}ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ8.62 (s, 1 H), 8.45 (d, J = 2.4 Hz, 1 H), 8.38 (s, 1 H), 7.75-7.70 (m, 1H), 6.91 (t, J = 51.6 Hz, 1 H), 5.35 (s, 2 H), 3.78-3.69 (m, 4 H), 3.34(t, J = 6.8 Hz, 2 H), 2.94 (t, J = 6.4 Hz, 2 H), 2.87-2.86 (m, 2 H),2.72-2.68 (m, 2 H), 2.49-2.46 (m, 2 H). LCMS RT = 0.417 min, m/z = 531.20.010 I-181 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[(5- fluoropyridin-2-yl)methyl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.44 (t, J = 2.0 Hz, 1 H), 8.41(s, 1 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.42 (s, 1 H), 6.92 (t, J = 51.6Hz, 1 H), 4.86 (s, 2 H), 4.65 (s, 2 H), 3.23 (q, J = 7.2 Hz, 2 H), 1.42(t, J = 7.2 Hz, 3 H). LCMS RT = 1.338 min, m/z = 434.2 3.46 I-182Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- fluoropyridin-3-yl)-2-{3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.61 (s, 1 H), 8.46 (d, J = 2.4 Hz, 1 H), 8.39 (s, 1 H),7.72-7.65 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.35 (s, 2 H), 4.19 (d,J = 11.2 Hz, 2 H), 3.78 (d, J = 11.2 Hz, 2 H) 3.56 (d, J = 6.4 Hz, 2 H),3.29-3.25 (m, 2 H), 3.21-3.18 (m, 2 H), 2.70- 2.65 (m, 1 H), 1.89 (d, J= 8.4 Hz, 1 H) LCMS RT = 0.844 min, m/z = 517.3 0.018 I-183 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[(pyridin-2-yl)methyl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J =4.4 Hz, 1 H), 8.40 (s, 1 H), 7.76- 7.69 (m, 1 H), 7.39 (d, J = 7.6 Hz, 1H), 7.25 (s, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 4.89 (s, 2 H), 4.68 (s, 2H), 3.25 (q, J = 7.2 Hz, 2 H), 1.42 (t, J = 7.2 Hz, 3 H). LCMS RT =0.932 min, m/z = 416.2 2.54 I-184 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl]-N-(pyridin-3- yl)ethane-1-sulfonamide 1HNMR (400 MHz, CDCl3) δ 8.73 (d, J = 2.4 Hz, 1 H), 8.60 (d, J = 3.2 Hz, 1H), 8.39 (s, 1 H), 7.89-7.82 (m, 1 H), 7.40-7.33 (m, 1 H), 6.91 (t, J =51.6 Hz, 1 H), 5.31 (s, 2 H), 4.53 (d, J = 6.4 Hz, 2 H), 3.46-3.42 (m, 2H), 3.21- 3.02 (m, 5 H), 2.86 (d, J = 11.2 Hz, 2 H), 2.29 (d, J = 8.4Hz, 1 H). LCMS RT = 1.352 min, m/z = 498.9 0.014 I-185 Example 2

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholin-4-yl)-N-(pyridin-3-yl)propanamide 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J =4.4 Hz, 1 H), 8.55 (d, J = 2.4 Hz, 1 H), 8.38 (s, 1 H), 7.63 (d, J = 8.0Hz, 1 H), 7.43-7.39 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.21 (s, 2 H),3.65 (t, J = 4.4 Hz, 4 H), 2.73 (t, J = 7.2 Hz, 2 H), 2.38-2.33 (m, 6H). LCMS RT = 0.411 min, m/z = 451.2 0.516 I-186 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(1,4-oxazepan-4- yl)ethane-1-sulfonamide 1H NMR(400 MHz, CDCl3) δ 8.58 (s, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 8.40 (s, 1H), 7.70-7.67 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.32 (s, 2 H), 3.81(t, J = 6.4 Hz, 2 H), 3.75 (t, J = 4.8 Hz, 2 H), 3.41 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.6 Hz, 2 H) 2.84-2.76 (m, 4 H), 1.97- 1.92 (m, 2 H).LCMS RT = 0.414 min, m/z = 519.2 0.0276 I-187 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-[(1S,4S)-2-oxa-5-azabicydo[2.2.1]heptan-5-yl]-N- (pyridin-3-yl)ethane-1-sulfonamide1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 2.4 Hz, 1 H), 8.60-8.57 (m, 1 H),8.38 (s, 1 H), 7.88-7.85 (m, 1 H), 7.40- 7.26 (m, 1 H), 6.91 (t, J =51.6 Hz, 1 H), 5.37-5.25 (m, 2 H), 4.47 (s, 1 H), 4.02 (d, J = 8.4 Hz, 1H), 3.70-3.55 (m, 1 H), 3.58 (s, 1 H), 3.36 (t, J = 6.8 Hz, 2 H),3.22-3.09 (m, 2 H), 3.00-2.92 (m, 1 H), 2.60 (d, J = 9.6 Hz, 1 H), 1.86-1.80 (m, 2 H). LCMS RT = 0.429 min, m/z = 499.2 0.0247 I-188 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(5-fluoropyridin-3-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.58 (s, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 8.39 (s, 1 H),7.69-7.66 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.37-5.27 (m, 2 H), 4.47(s, 1 H), 4.02 (d, J = 8.0 Hz, 1 H), 3.68 (dd, J = 8.4, 1.6 Hz, 1 H),3.58 (s, 1 H), 3.38 (t, J = 6.8 Hz, 2 H), 3.22-3.09 (m, 2 H), 2.98-2.96(m, 1 H), 2.60 (d, J = 10.0 Hz, 1 H), 1.85-1.83 (m, 2 H). LCMS RT =0.457 min, m/z = 517.2 0.0151 I-189 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-2-[(2S)-2-methylmorpholin-4-yl]-N-(pyridin-3- yl)ethane-1-sulfonamide 1H NMR (400MHz, CDCl3) δ 8.73 (d, J = 2.4 Hz, 1 H), 8.59 (d, J = 3.6 Hz, 1 H), 8.38(s, 1 H), 7.88-7.85 (m, 1 H), 7.39-7.35 (m, 1 H), 6.91 (t, J = 51.6 Hz,1 H), 5.32 (s, 2 H), 3.91-3.88 (m, 1 H), 3.71-3.62 (m, 2 H), 3.38 (t, J= 6.8 Hz, 2 H), 2.90 (t, 1 = 7.2 Hz, 2 H), 2.76- 2.69 (m, 2 H),2.28-2.21 (m, 1 H), 1.93 (t, J = 10.8 Hz, 1 H), 1.17 (d, J = 6.0 Hz, 3H). LCMS RT = 1.427 min, m/z = 500.9 0.0363 I-190 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-{3-oxa-6- azabicyclo[3.1.1]heptan-6-yl}ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.4 Hz, 1 H), 8.54(d, J = 2.4 Hz, 1 H), 8.39 (s, 1 H), 7.95 (t, J = 2.4 Hz, 1 H), 6.91 (t,J = 51.6 Hz, 1 H), 5.34 (s, 2 H), 4.21 (d, J = 11.6 Hz, 2 H), 3.80 (d, J= 11.2 Hz, 2 H), 3.60 (d, J = 6.0 Hz, 2 H), 3.32-3.25 (m, 2 H),3.24-3.17 (m, 2 H), 2.77-2.63 (m, 1 H), 1.91 (d, J = 8.4 Hz, 1 H). LCMSRT = 0.968 min, m/z = 533.2 0.016 I-191 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-{6-oxa-3- azabicyclo[3.1.1]heptan-3-yl}ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 2.0 Hz, 1 H), 8.55(d, J = 2.0 Hz, 1 H), 8.41 (s, 1 H), 7.90 (t, J = 2.4 Hz, 1 H), 6.91 (t,1 = 51.2 Hz, 1 H), 5.29 (s, 2 H), 4.52 (d, 1 = 6.4 Hz, 2 H), 3.43 (t, J= 6.8 Hz, 2 H), 3.18 (t, J = 7.2 Hz, 2 H), 3.10 (d, 1 = 10.8 Hz, 2 H),3.06-2.80 (m, 3 H), 2.28 (d, J = 8.0 Hz, 1 H). LCMS RT = 0.482 mm, m/z =533.2 0.0124 I-192 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- fluoropyridin-3-yl)-2-{6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.57 (s, 1 H), 8.46 (d, J = 2.4 Hz, 1 H), 8.40 (s, 1 H),7.73-7.61 (m, 1 H), 6.92 (t, J = 51.2 Hz, 1 H), 5.31 (s, 2 H), 4.52 (d,J = 6.0 Hz, 2 H), 3.46 (t, J = 6.8 Hz, 2 H), 3.18 (t, J = 7.6 Hz, 2 H),3.12 (d, J = 11.0 Hz, 2 H), 3.08-3.01 (m, 1 H), 2.86 (d, J = 11.2 Hz, 2H), 2.27 (d, J = 8.0 Hz, 1 H). LCMS RT = 1.368 min, m/z = 517.2 0.0168I-193 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-(1,4-oxazepan-4-yl)-N-(pyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ ppm8.73 (d, J = 2.4 Hz, 1 H), 8.58 (d, J = 4.0 Hz, 1 H), 8.38 (s, 1 H),7.86 (d, J = 8.0 Hz, 1 H), 7.39-7.35 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1H), 5.32 (s, 2 H), 3.80 (t, J = 6.0 Hz, 2 H), 3.75-3.73 (m, 2 H), 3.37(t, J = 7.6 Hz, 2 H), 3.10 (t, J = 6.4 Hz, 2 H), 2.79-2.75 (m, 4 H),1.95- 1.91 (m, 2 H). LCMS RT = 0.429 min, m/z = 501.2 0.0203 I-194Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-[(2R)-2-methylmorpholin-4-yl]-N-(pyridin-3- yl)ethane-1-sulfonamide 1H NMR (400MHz, CDCl3) δ ppm 8.73 (s, 1 H), 8.59 (d, J = 4.4 Hz, 1 H), 8.38 (s, 1H), 7.86-7.83 (m, 1 H), 7.38- 7.35 (m, 1 H), 6.91 (t, J = 51.2 Hz, 1 H),5.31 (s, 2 H), 3.87-3.67 (m, 1 H), 3.66-3.64 (m, 2 H), 3.64 (t, 1 = 6.8Hz, 2 H), 2.89 (t, J = 6.8 Hz, 2 H), 2.74- 2.67 (m, 2 H) 2.24-2.23 (m, 1H), 1.92 (t, J = 6.8 Hz, 1 H), 1.17 (d, J = 6.8 Hz, 3H). LCMS RT = 0.748mm. m/z = 501.2 0.0267 I-195 Example 2

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-(morpholin-4- yl)propanamide 1H NMR (400 MHz,CDCl3) δ ppm 8.62 (s, 1 H), 8.44 (s, 1 H), 8.39 (s, 1 H), 7.72 (s, 1 H),6.92 (t, J = 51.6 Hz, 1 H), 5.18 (s, 2 H), 3.17-3.69 (m, 8 H), 2.86-2.83 (m, 2 H), 2.44-2.41 (m, 2 H). LCMS RT = 1.381 min, m/z = 485.30.312 I-196 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-N-(pyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.59 (d, J = 4.0 Hz, 1 H), 8.39 (s, 1 H), 7.87 (d, J = 8.4Hz, 1 H),7.39-7.35 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.36- 5.27 (m, 2 H),4.48 (s, 1 H), 4.05 (d, J = 8.4 Hz, 1 H), 3.70-3.66 (m, 2 H), 3.43 (t, J= 6.8 Hz, 2 H), 3.26-3.13 (m, 2 H), 3.03 (d, J = 10.0 Hz, 1 H), 2.66 (d,1 = 10.4 Hz, 1 H), 1.95-1.85 (m, 2 H). LCMS RT = 1.117 min, m/z = 499.20.0497 I-197 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-[(2R)-2-methylmorpholin-4-yl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.63(d, J = 2.0 Hz, 1 H), 8.54 (d, J = 2.0 Hz, 1 H), 8.39 (s, 1 H), 7.91 (t,J = 2.0 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.30 (s, 2 H), 3.93-3.85(m, 1 H), 3.72-3.60 (m, 2 H), 3.36 (t, J = 6.8 Hz, 2 H), 2.88 (t, J =6.8 Hz, 2 H), 2.75-2.65 (m, 2 H), 2.28-2.17 (m, 1 H), 1.91 (t, J = 10.8Hz, 1 H), 1.17 (d, J = 6.4 Hz, 3 H). LCMS RT = 1.558 min, m/z = 535.20.0472 I-198 Example 2

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propanamide 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1 H),8.44-8.35 (m, 2 H), 7.67 (t, J = 2.0 Hz, 1 H), 6.92 (t, J = 51.6 Hz, 1H), 5.18 (s, 2 H), 2.18 (q, J = 7.2Hz, 2 H), 1.13(t, J = 7.6 Hz, 3 H).LCMS RT = 1.929 min, m/z = 400.2 0.299 I-199 Example 2

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(pyridin-3- yl)propanamide 1H NMR (400MHz, CDCl3) δ 8.64 (d, J = 4.0 Hz, 1 H), 8.53 (s, 1 H), 8.37 (s, 1 H),7.61 (d, J = 8.0 Hz, 1 H), 7.42-7.36 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1H), 5.20 (s, 2 H), 2.15 (q, J = 7.2 Hz, 2 H), 1.12 (t, J = 7.2 Hz, 3 H).LCMS RT = 1.372 min, m/z = 366.2 0.355 I-200 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)- 1H,2H,3H,4H,5H-pyrido[4,3-b]azepin-2-one1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 5.2 Hz, 1 H), 8.46 (s, 1 H), 8.39(s, 1 H), 7.36 (d, J = 5.6 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.33(s, 2 H), 2.80 (t, J = 7.2 Hz, 2 H), 2.44 (t, J = 7.2 Hz, 2 H),2.36-2.24 (m, 2 H). LCMS RT = 0.993 min, m/z = 378.2 0.125 I-201 Example4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(5-fluoropyridin-3-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.57 (s, 1 H), 8.46 (d, J = 2.4 Hz, 1 H), 8.39 (s, 1 H),7.70-7.62 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.39-5.25 (m, 2 H), 4.46(s, 1 H), 4.00 (d, J = 8.0 Hz, 1 H), 3.69- 3.64 (m, 1 H), 3.52 (s, 1 H),3.34 (t, J = 6.8 Hz, 2 H), 3.19-3.07 (m, 2 H), 2.94 (d, J = 10.0 Hz, 1H), 2.56 (d, 1 = 10.0 Hz, 1H), 1.89-1.79 (m, 2 H). LCMS RT = 0.459 min,m/z = 517.2 0.0207 I-202 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-[(2S)-2-methylmorpholin-4-yl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.63(s, 1 H), 8.54 (s, 1 H), 8.39 (s, 1 H), 7.91 (s, 1 H), 6.91 (t, J = 51.2Hz, 1 H), 5.30 (s, 2 H), 3.94-3.85 (m, 1 H), 3.74-3.62 (m, 2 H), 3.43(t, J = 6.8 Hz, 2 H), 2.88 (t, J = 6.8 Hz, 2 H), 2.72 (t, J = 12.8 Hz, 2H), 2.28-2.17 (m, 1 H), 1.92 (t, J = 9.6 Hz, 1 H), 1.17 (d, J = 6.0 Hz,3 H). LCMS RT = 1.561 min, m/z = 535.2 0.0127 I-203 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- fluoropyridin-3-yl)-2-[(2S)-2-methylmorpholin-4-yl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.58(s, 1 H), 8.47 (d, 1 = 2.4 Hz, 1 H), 8.40 (s, 1 H), 7.68 (d, J = 9.2 Hz,1 H), 6.92 (t, J = 51.2 Hz, 1 H), 5.32 (s, 2 H), 3.91-3.71 (m, 1 H),3.72-3.64 (m, 2 H), 3.41 (t, J = 6.8 Hz, 2 H), 2.91 (t, J = 7.2 Hz, 2H), 2.73 (t, J = 12.8 Hz, 2 H), 2.29-2.22 (m, 1 H), 1.96-1.94 (m, 1 H),1.17 (d, J = 6.4 Hz, 3 H). LCMS RT = 1.660 mm, m/z = 519.0 0.0254 I-204Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(5- fluoropyridin-3-yl)-2-[(2R)-2-methylmorpholin-4-yl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.58(s, 1 H), 8.47 (s, 1 H), 8.40 (s, 1 H), 7.70- 7.66 (m, 1 H), 6.91 (t, J= 51.6 Hz, 1 H), 5.32 (s, 2 H), 3.89 (d, J = 9.6 Hz, 1 H), 3.70-3.60 (m,2 H), 3.37 (t, J = 6.8 Hz, 2 H), 2.88 (t, J = 6.8 Hz, 2 H), 2.72- 2.65(m, 2 H), 2.26-2.20 (m, 1 H), 1.91 (t, J = 10.4 Hz, 1 H), 1.17 (d, J =6.0 Hz, 3 H). LCMS RT = 1.664 min, m/z = 518.9 0.0336 I-205 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.62 (d, J = 2.0 Hz, 1 H), 8.54 (d, J = 2.0 Hz, 1 H), 8.40 (s,1 H), 7.91 (t, J = 2.0 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.40- 5.21(m, 2 H), 4.47 (s, 1 H), 4.02 (d, J = 8.0 Hz, 1 H), 3.68-3.63 (m, 1 H),3.56 (s, 1 H), 3.35 (t, J = 6.8 Hz, 2 H), 3.25- 3.05 (m, 2 H), 3.01-2.90(m, 1 H), 2.59 (d, J = 10.0 Hz, 1 H), 1.93-1.80 (m, 2 H). LCMS RT =0,919 min, m/z = 533.2 0.0159 I-206 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.62 (d, J = 2.0 Hz, 1 H), 8.54 (d, J = 2.0 Hz, 1 H), 8.39 (s,1 H), 7.91 (t, J = 2.0 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.37- 5.25(m, 2 H), 4.46 (s, 1 H), 4.01 (d, J = 8.4 Hz, 1 H), 3.69-3.62 (m, 1 H),3.51 (s, 1 H), 3.31 (t, J = 6.8 Hz, 2 H), 3.18- 3.07 (m, 2 H), 2.93 (d,J = 10.0 Hz, 1 H), 2.56 (d, J = 9.6 Hz, 1 H), 1.89-1.84 (q, J = 7.2 Hz,2 H). LCMS RT = 0.472 min, m/z = 533.2. 0.0162 I-207 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}ethane-1- sulfonamide 1H NMR (400 MHz, CDCl3) δ8.67 (d, J = 2.4 Hz, 1 H), 8.56 (s, 1 H), 8.39 (s, 1 H), 7.83 (s, 1 H),6.91 (t, J = 51.6 Hz, 1 H), 5.79-5.60 (m, 1 H), 5.30 (s, 2 H), 3.21 (q,J = 7.2 Hz, 2 H), 1.69-1.55 (m, 3 H), 1.46 (t, J = 7.6 Hz, 3 H). LCMS RT= 1.500 min, m/z = 447.8 0.0137 I-208 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl}ethane-1- sulfonamide 1H NMR (400 MHz, CDCl3) δ8.67 (d, J = 2.0 Hz, 1 H), 8.56 (s, 1 H), 8.39 (s, 1 H), 7.83 (s, 1 H),6.91 (t, J = 52.0 Hz, 1 H), 5.78-5.62 (m, 1 H), 5.30 (s, 2 H), 3.21 (q,J = 7.2 Hz, 2 H), 1.74-1.62 (m, 3 H), 1.46 (t, J = 7.6 Hz, 3 H). LCMS RT= 1.503 min, m/z = 447.8 0.027 I-209 Example 2

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- fluoropyridin-3-yl)propanamide 1H NMR(400 MHz, CDCl3) δ 8.54 (d, J = 2.4 Hz, 1 H), 8.39-8.35 (m, 2 H),7.44-7.40 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1 H) 5.19 (s, 2 H), 2.19 (q, J= 6.8 Hz, 2 H), 1.13 (t, J = 7.6 Hz, 3 H). LCMS RT = 1.755 min, m/z =384.2 0.284 I-210 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1,2,3,4- tetrahydro-1,6-naphthyridin-2-one1H NMR (400 MHz, CDCl₃) δ 8.49- 8.37 (m, 3 H), 7.19 (d, J = 5.6 Hz, 1H), 6.89 (t, J = 51.6 Hz, 1 H), 5.46 (s, 2 H), 3.10-3.01 (m, 2 H),2.91-2.80 (m, 2 H). LCMS RT = 0.971 min, m/z = 364.2 0.0487 I-211Example 4

  (2R)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(pyridin-3-yl)butane-2-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.57-8.55 (m, 1 H), 8.35 (s, 1 H), 7.87-7.82 (m, 1 H), 7.38-7.32 (m,1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.38- 5.20 (m, 2 H), 3.14-3.06 (m, 1H), 2.13-2.05 (m, 1 H), 1.72-1.65 (m, 1 H), 1.45 (d, 1 = 6.8 Hz, 3 H),1.04 (t, J = 7.6 Hz, 3 H). LCMS RT = 0.563 min, m/z = 430.1 0.0137 I-212Example 4

  (2S)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(pyridin-3-yl)butane-2-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.58-8.55 (m, 1 H), 8.35 (s, 1 H), 7.89-7.86 (m, 1 H), 7.34 (q, J =4.8 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.39- 5.23 (m, 2 H), 3.14-3.06(m, 1 H), 2.14- 2.04 (m, 1 H), 1.74-1.65 (m, 1 H), 1.45 (d, J = 6.8 Hz,3 H), 1.04 (t, 1 = 7.6 Hz, 3 H). LCMS RT = 0.563 min, m/z = 430.1 0.0105I-213 Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-(morpholin-4- yl)ethane-1-sulfonamide 1H NMR (400MHz, CDCl3) δ 8.96 (d, J = 2.4 Hz, 1 H), 8.82 (s, 1 H), 8.41 (s, 1 H),8.19 (s, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.33 (s, 2 H), 3.74 (t, J =4.8 Hz, 4 H), 3.38 (t, J = 6.8 Hz, 2 H), 2.89 (t, J = 7.2 Hz, 2 H), 2.50(t, J = 4.8 Hz, 4 H). LCMS RT = 1.295 min, m/z = 512.2 0.0902 I-214Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-(morpholin-4-yl)ethane- 1-sulfonamide 1H NMR (400MHz, CDCl3) δ ppm 8.59 (s, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 8.40 (s, 1H), 7.71-7.67 (m, 1 H), 6.93 (t, J = 51.6 Hz, 1 H), 5.33 (s, 2 H), 3.78-3.72 (m, 4 H), 3.40 (t, J = 6.8 Hz, 2 H), 2.91 (t, J = 6.8 Hz, 2 H),2.53-2.51 (m, 4 H). LCMS RT = 0.908 min, m/z = 505.2 0.0154 I-215Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(pyridin-3- yl)butane-2-sulfonamide 1HNMR (400 MHz, CDCl3) δ 8.72 (d, J = 2.8 Hz, 1 H), 8.58-8.56 (m, 1 H),8.35 (s, 1 H), 7.89-7.86 (m, 1 H), 7.36 (q, J = 4.8 Hz, 1 H), 6.91 (t, J= 51.6 Hz, 1 H), 5.37-5.26 (m, 2 H), 3.14-3.05 (m, 1 H), 2.12-2.06 (m, 1H), 1.75- 1.69 (m, 1 H), 1.45 (d, J = 6.8 Hz, 3 H), 1.04 (t, J = 7.6 Hz,3 H). LCMS RT = 0.560 min, m/z = 430.1 0.00675 I-216 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{5-[(1S)-1-fluoroethyl]pyridin-3-yl}methanesulfonamide 1H NMR (400 MHz, CDCl3) δ8.68 (s, 1 H), 8.58 (s, 1 H), 8.42 (s, 1 H), 7.84 (s, 1 H), 6.92 (t, J =51.6 Hz, 1 H), 5.80- 5.61 (m, 1 H), 5.29 (s, 2 H), 3.11 (s, 3 H),1.75-1.55 (m, 3 H). LCMS RT = 0.550 min, m/z = 434.1 0.0119 I-217Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-{5-[(1R)-1-fluoroethyl]pyridin-3-yl]methanesulfonamide 1H NMR (400 MHz, CDCl3) δ8.70 (s, 1 H), 8.58 (s, 1 H), 8.42 (s, 1 H), 7.86 (s, 1 H), 6.92 (t, J =51.6 Hz, 1 H), 5.81- 5.60 (m, 1 H), 5.29 (s, 2 H), 3.11 (s, 3 H),1.75-1.55 (m, 3 H). LCMS RT = 0.551 min, m/z = 434.1 0.0236 I-218Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethyl)pyridin-3-yl]methanesulfonamide 1H NMR (400 MHz, CDCl3) δ8.68 (d, J = 2.4 Hz, 1 H), 8.57 (s, 1 H), 8.41 (s, 1 H), 7.84 (s, 1 H),6.91 (t, J = 51.2 Hz, 1 H), 5.79-5.62 (m, 1 H), 5.28 (s, 2 H), 3.11 (s,3 H), 1.75-1.55 (m, 3 H). LCMS RT = 0.545 min, m/z = 434.1 0.0369 I-219Example 4

  2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-methylpyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ8.52 (d, J = 2.0 Hz, 1 H), 8.47 (s, 1 H), 8.45 (s, 1 H), 7.65 (s, 1 H),6.92 (t, J = 51.6 Hz, 1 H), 5.28 (s, 2 H), 3.53 (t, J = 7.6 Hz, 2 H),2.98 (t, J = 7.2 Hz, 2 H), 2.39 (s, 3 H). LCMS RT = 0.507 min, m/z =441.1 0.0202 I-220 Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-2-(morpholin-4- yl)ethane-1-sulfonamide 1H NMR (400MHz, CDCl3) δ 8.61 (s, 1 H), 8.46 (s, 1 H), 8.39 (s, 1 H), 7.70 (s, 1H), 6.91 (t, J = 51.6 Hz, 1 H), 6.59 (t, J = 72.0 Hz, 1 H), 5.31 (s, 2H), 3.77- 3.69 (m, 4 H), 3.38 (t, J = 6.8 Hz, 2 H), 2.89 (t, J = 7.2 Hz,2 H), 2.54-2.46 (m, 4 H). LCMS RT = 1.504 min, m/z = 553.2 0.0184 I-221Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(6-ethylpyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.58(d, J = 2.4 Hz, 1 H), 8.37 (s, 1 H), 7.75- 7.70 (m, 1 H), 7.22 (d, J =8.4 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.7 (s, 2 H), 3.20 (q, J = 7.6Hz , 2 H), 2.83 (q, J = 7.6 Hz , 2 H), 1.46 (t, J = 7.2 Hz, 3 H), 1.30(t, J = 7.6 Hz, 3 H). LCMS RT = 1.134 min, m/z = 430.2 0.033 I-222Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2- fluoropropan-2-yl)pyridin-3-yl]methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 2.0 Hz, 1H), 8.60 (s, 1 H), 8.42 (s, 1 H), 7.86 (t, J = 2.0 Hz, 1 H), 6.92 (t, J= 51.6 Hz, 1 H), 5.28 (s, 2 H), 3.11 (s, 3 H), 1.75 (s, 3 H), 1.69 (s,3H). LCMS RT = 1.499 min, m/z = 447.9 0.0376 I-223 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5-fluoropyridin-3-yl)-2-methylpropane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.58 (s, 1 H), 8.47 (d, J = 2.8 Hz, 1 H), 8.40 (s, 1 H),7.68-7.62 (m, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.29 (s, 2 H), 3.05 (d,J = 2.0 Hz, 2 H), 2.40-2.30 (m, 1 H), 1.12 (d, J = 6.8 Hz, 6 H). LCMS RT= 1.790 min, m/z = 447.9 0.00563 I-224 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2- difluoropropoxy)pyridin-3-yl]methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1 H), 8.39-8.33(m, 2 H), 7.48-7.41 (m, 1 H), 6.92 (t, J = 51.6 Hz, 1 H), 5.28 (s, 2 H),4.18 (t, J = 11.2 Hz, 2 H), 3.11 (s, 3 H), 1.79 (t, J = 18.8 Hz, 3 H).LCMS RT = 1.492 min, m/z = 482.2 0.0204 I-225 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2,2-difluoropropoxy)pyridin-3-yl]ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.42- 8.36 (m, 2 H), 8.33 (s, 1 H), 7.45 (s, 1 H) 6.91 (t, J =51.6 Hz, 1 H), 5.30 (s, 2 H) 4.17 (t, J = 11.2 Hz, 2 H), 3.21 (q, J =7.6 Hz, 2 H), 1.79 (t, 1 = 18.8 Hz, 3 H), 1.46 (t, J = 7.6 Hz, 3 H).LCMS RT = 1.559 min, m/z = 496.2 0.00601 I-226 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(2-fluoropropan-2-yl)pyridin-3-yl]ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.66 (d, J = 2.4 Hz, 1 H), 8.59 (d, J = 1.2 Hz, 1 H) 8.40 (s, 1H), 7.91-7.86 (m, 1 H), 6.91 (t, J = 5 1.6 Hz, 1 H), 5.30 (s, 2 H), 3.21(q, J = 6.8 Hz, 2 H), 1.75 (s, 3 H), 1.69 (s, 3 H), 1.47 (E, J = 6.4 Hz,3 H). LCMS RT = 1.510 min, m/z = 462.2 0.0319 I-227 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5-(1-fluoroethyl)pyridin-3-yl]ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ8.67 (d, J = 2.4 Hz, 1 H), 8.56 (s, 1 H), 8.39 (s, 1 H), 7.83 (s, 1 H),6.91 (t, J = 51.6 Hz, 1 H), 5.79-5.62 (m, 1 H), 5.30 (s, 2 H), 3.21 (q,J = 7.2 Hz, 2 H), 1.74-1.56 (m, 3 H), 1.47 (t, J = 7.2 Hz, 3 H). LCMS RT= 1.518 min, m/z = 447.9 0.0123 I-228 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(6- ethylpyridin-3-yl)methanesulfonamide1H NMR (400 MHz, CD3OD) δ 8.54 (d, J = 2.4 Hz, 1 H), 8.39 (s, 1 H),7.93- 7.88 (m, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.17 (t, J = 51.6 Hz, 1H), 5.31 (s, 2 H), 3.12 (s, 3 H), 2.78 (q, J = 7.6 Hz, 2 H) 1.24 (t, J =7.6 Hz, 3 H). LCMS RT = 0.981 min, m/z = 416.2 0.0435 I-229 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- ethylpyridin-3-yl)methanesulfonamide1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1 H), 8.42 (s, 1 H), 8.40 (s, 1 H),7.89 (s, 1 H), 7.18 (t, J = 51.6 Hz, 1 H), 5.35 (s, 2 H), 3.14 (s, 3 H),2.69 (q, J = 7.2 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H). LCMS RT = 1.099min, m/z = 416.2 0.0248 I-230 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(5- ethylpyridin-3-yl)-2-methoxyethane-1-sulfonamide 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J = 2.4 Hz, 1 H), 8.38(s, 1 H), 8.35 (s, 1 H), 7.88 (s, 1 H), 7.18 (t, J = 51.6 Hz, 1 H), 5.31(s, 2 H), 3.82 (t, J = 5.6 Hz, 2 H), 3.48 (t, J = 5.2 Hz, 2 H), 3.43 (s,3 H), 2.69 (q, J = 5.2 Hz, 2 H), 1.24 (t, J = 7.6 Hz, 3 H). LCMS RT =1.752 min, m/z = 460.2 0.033 I-231 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-y1}ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.39 (s, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 6.12 (s, 1 H), 5.38(s, 2 H), 4.77 (s, 2 H), 4.12- 1.06 (m, 4 H), 3.27 (q, J = 7.2 Hz, 2 H),1.42 (t, J = 7.6 Hz, 3H). LCMS RT = 0.552 min, m/z = 447.1 0.0924 I-232Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.63(d, J = 2.0 Hz, 1 H), 8.51 (d, J = 2.4 Hz, 1 H), 8.46 (s, 1 H), 7.70 (s,1 H), 6.61 (t, J = 71.6 Hz, 1 H), 5.30 (s, 2 H) 3.13 (s, 3 H). LCMS RT =1.766 min, m/z = 471.8 0.0342 I-233 Example 4

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.59(d, J = 2.0 Hz, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 8.42 (s, 1 H), 7.67 (t,J = 2.4 Hz, 1 H), 6.59 (t, J = 72.0 Hz, 1 H), 5.29 (s, 2 H), 3.19-3.11(m, 2H), 1.97-1.88 (m, 2 H), 1.08 (t, J = 7.6 Hz, 3 H). LCMS RT = 2.013min, m/z = 499.9 0.0606 I-234 Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.95(d, J = 2.4 Hz, 1 H), 8.82 (s, 1 H), 8.44 (s, 1 H), 8.16 (d, J = 2.4 Hz,1 H), 5.29 (s, 2 H), 3.18-3.11 (m, 2 H), 2.00-1.80 (m, 2 H), 1.09 (t, J= 7.2 Hz, 3 H). LCMS RT = 1.811 min, m/z = 459.2 0.184 I-235 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(1H-imidazol- 5-yl)ethane-1-sulfonamide1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1 H), 7.99 (s, 1 H), 7.39-7.03 (m, 2H), 5.30 (s, 2 H), 3.39-3.28 (m, 2 H), 1.40 (t, J = 7.2 Hz, 3 H). LCMSRT = 1.848 mm, m/z = 390.8 0.323 I-236 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-(6-methylpyridin-2-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.39(s, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.01 (s,1 H), 6.89 (t, J = 51.6 Hz, 1 H) 5.60 (s, 2 H), 3.27 (q, J = 7.6 Hz, 2H), 2.52 (s, 3 H), 1.37 (t, J = 7.4 Hz, 3 H). LCMS RT = 1.704 min, m/z =416.2 0.0592 I-237 Example 4

  N-(3-fluorophenyl)-N-({5-[5-(trifluorornethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.41(s, 1 H), 7.44-7.36 (m, 1 H), 7.30-7.27 (m, 1 H), 7.24-7.20 (m, 1 H),7.12- 7.05 (m, 1 H), 5.27 (s, 2 H), 3.07 (s, 3 H). LCMS RT = 1.912 min,m/z = 422.8 0.0992 I-238 Example 4

  N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5- (trifluoromethyl)pyridin-3-yl]methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.0 Hz, 1H), 8.87 (s, 1 H), 8.46 (s, 1 H), 8.12 (t, J = 2.0 Hz, 1 H), 5.31 (s, 2H), 3.12 (s, 3 H). LCMS RT = 1.905 min, m/z = 473.8 0.256 I-239 Example4

  N-(5-cyclopropylpyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.46(s, 1 H), 8.42 (s, 1 H), 8.37 (s, 1 H), 7.45 (t, J = 2.4 Hz, 1 H), 5.26(s, 2 H), 3.09 (s, 3 H), 2.00 1.90 (m, 1 H), 1.11-1.08 (m, 2 H),0.78-0.75 (m, 2 H). LCMS RT = 1.621 min, m/z = 445.9 0.085 I-240 Example4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.62(s, 1 H), 8.57 (s, 1 H), 7.89 (s, 1 H), 5.28 (s, 2 H), 3.11 (s, 3 H).LCMS RT = 2.259 min, m/z = 440.1 0.062 I-241 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-[5-(2-methoxyethyl)pyridin-3-yl]ethane-1- sulfonamide 1H NMR (400 MHz, CDCl3)δ 8.50 (s, 1 H), 8.48 (s, 1 H), 7.80 (s, 1 H), 7.65 (s, 1 H), 6.92 (t, J= 51.6 Hz, 1 H), 5.80 (s, 2 H), 3.60 (t, J = 6.0 Hz, 2 H), 3.33 (s, 3H), 3.08 (q, J = 7.2 Hz, 2 H), 2.85 (t, J = 6.0 Hz, 2 H), 1.40 (t, J =7.6 Hz, 3 H). LCMS RT = 0.718 min, m/z = 460.2 0.994 I-242 Example 4

  N-(3-fluorophenyl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.41(s, 1 H), 7.43-7.37 (m, 1 H), 7.27-7.26 (m, 1 H), 7.25-7.22 (m, 1 H),7.10- 7.05 (m, 1 H), 5.30 (s, 2 H), 3.15-3.10 (m, 2 H), 1.97-1.89 (m, 2H), 1.09 (t, J = 7.2 Hz, 3 H). LCMS RT = 2.207 min, m/z = 450.8 0.053I-243 Example 4

  N-(5-cyanopyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.96(d, J = 2.4 Hz, 1 H), 8.82 (d, J = 2.0 Hz, 1 H), 8.44 (s, 1 H), 8.17 (t,J = 2.0 Hz, 1 H), 5.30 (s, 2 H), 3.21 (q, J = 7.2 Hz, 2 H), 1.45 (t, J =7.2 Hz, 3 H). LCMS RT = 1.718 min, m/z = 444.8 0.129 I-244 Example 4

  N-(5-chloropyridin-3-yl)-N-({5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)propane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.61(d, J = 2.4 Hz, 1 H), 8.55 (d, J = 2.4 Hz, 1 H), 8.42 (s, 1 H), 7.88 (t,J = 2.0 Hz, 1 H), 5.28 (s, 2 H), 3.19-3.11 (m, 2 H), 1.97-1.82 (m, 2 H),1.09 (t, J = 7.6 Hz, 3 H). LCMS RT = 2.027 min, m/z = 467.8 0.0872 I-245Example 2

  (3R)-1-{(5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-methyl-1H,2H,3H,4H,5H-pyrido[3 4- b]azepin-2-one 1H NMR (400 MHz, CDCl3)δ 8.96 (s, 1 H), 8.52 (d, J = 5.2 Hz, 1 H), 8.38 (s, 1 H), 7.52 (d, J =5.2 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H) 5.47-5.27 (m, 2 H), 3.09- 3.04(m, 1 H), 2.83-2.78 (m, 1 H), 2.51-2.47 (m, 1 H), 2.26-2.21 (m, 1 H),2.18-2.11 (m, 1 H), 1.16 (d, J = 6.4 Hz, 3 H) LCMS RT = 1.250 min, m/z =392.3. 1.42 I-246 Example 2

  (3S)-1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-methyl-1H,2H,3H,4H,5H-pyrido[3,4- b]azepin-2-one 1H NMR (400 MHz, CDCl3)δ 8.91 (s, 1 H), 8.50 (d, J = 5.2 Hz, 1 H), 8.37 (s, 1 H), 7.47 (d, J =5.2 Hz, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.46-5.28 (m, 2 H), 3.11- 2.85(m, 1 H), 2.84-2.71 (m, 1 H). 2.548-2.45 (m, 1 H), 2.29-2.14 (m, 1 H),2.18-2.07 (m, 1 H), 1.16 (d, J = 6.4 Hz, 3 H) LCMS RT = 1.251 min, m/z =392.3. 0.039 I-247 Example 2

  1-(5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1′,2′-dihydrospiro[cyclopropane-1,3′-pyrrolo[2,3- c]pyridin)-2′-one 1H NMR(400 MHz, CDCl3) δ 8.47 (s, 1 H), 8.44-8.40 (m, 2 H) 7.07 (d, J = 5.2Hz, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.43 (s, 2 H), 2.17-2.10 (m, 2 H),1.93- 1.86 (m, 2 H) LCMS RT = 0.970 min, m/z = 376.2. 0.158 I-248Example 2

  (4S)-1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-4-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2- one 1H NMR (400 MHz,CDCl3) δ 8.54 (s, 1 H), 8.41 (s, 1 H), 8.35 (d, J = 4.8 Hz, 1 H), 7.19(d, J = 4.8 Hz, 1 H), 6.89 (t, J = 51.6 Hz, 1 H), 5.62-5.46 (m, 2 H),3.23- 3.16 (m, 1 H), 2.92-2.84 (m, 1 H). 2.66-2.55 (m, 1 H), 1.38 (d, J= 6.8 Hz, 3H) LCMS RT = 1.098 min, m/z = 378.3. 0.034 I-249 Example 2

  (4R)-1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-4-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2- one 1H NMR (400 MHz,CDCl3) δ 8.53 (s, 1 H), 8.40 (s, 1 H), 8.34 (d, J = 4.8 Hz, 1 H), 7.18(d, J = 4.8 Hz, 1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.60-5.46 (m, 2 H),3.23- 3.15 (m, 1 H), 2.90-2.81 (m, 1 H), 2.64-2.55 (m, 1 H), 1.38 (d, J= 6.8 Hz, 3H) LCMS RT = 1.028 min, m/z = 378.2. 0.089 I-250 Example 2

  (3R)-1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2- one 1H NMR (400 MHz,CDCl3) δ 8.54 (s, 1 H), 8.41 (s, 1 H), 8.31 (d, J = 3.6 Hz, 1 H) 7.18(d, J = 4.4 Hz, 1 H), 6.89 (t, J = 51.6 Hz, 1 H), 5.62-5.36 (m, 2 H),3.09- 3.02 (m, 1 H), 2.89-2.79 (m, 2 H), 1.35 (d, J = 6.8 Hz, 3H) LCMSRT = 0.684 min, m/z = 378.2. 0.041 I-251 Example 2

  (3S)-1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2- one 1H NMR (400 MHz,CDCl3) δ 8.52 (s, 1 H), 8.41 (s, 1 H), 8.30 (d, J = 4.4 Hz, 1 H), 7.17(d, J = 4.8 Hz, 1 H), 6.89 (t, J = 51.6 Hz, 1 H), 5.62-5.36 (m, 2 H),3.09- 3.02 (m, 1 H), 2.89-2.79 (m, 2 H), 1.34 (d, J = 6.8 Hz, 3 H). LCMSRT = 0.521 min, m/z = 378.2. 0.034 I-252 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-methyl-1H,2H,3H,4H,5H-pyrido[3,4-b]azepin-2-one 1H NMR (400 MHz, CDCl3) δ 8.77(s, 1 H), 8.46 (d, J = 4.8 Hz, 1 H), 8.37 (s, 1 H), 7.30 (d, J = 4.4 Hz,1 H), 6.90 (t, J = 51.6 Hz, 1 H), 5.37 (s, 2 H), 2.99-2.90 (m, 1 H),2.70-2.66 (m, 1 H), 2.55- 2.49 (m, 1 H), 2.23-2.14 (m, 1 H), 2.18- 2.04(m, 1 H), 1.16 (d, J = 6.4 Hz, 3 H). LCMS RT = 1.229 min, m/z = 392.3.0.073 I-253 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3,3-dimethyl-1H,2H,3H,4H,5H-pyrido[3,4-b]azepin-2-one 1H NMR (400 MHz, CDCl3) δ 8.84(s, 1 H), 8.47 (s, 1 H), 8.40 (s, 1 H), 7.42 (s, 1 H), 6.91 (t, J = 51.6Hz, 1 H), 5.37 (s, 2H), 2.91 (t, J = 6.0 Hz, 2 H), 2.18 (t, J = 6.4 Hz,2 H), 1.04 (s, 6 H) LCMS RT = 1.946 min, m/z = 405.9. 0.035 I-254Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[2,3-c]pyridin-2-one 1H NMR (400 MHz, CDCl3) δ 8.45-8.43 (m, 2 H), 8.29 (s, 1 H), 7.24 (d, J = 4.8 Hz, 1 H), 6.89 (t, J =51.6 Hz, 1 H). 5.33 (s, 2 H), 1.49 (s, 6 H) LCMS RT = 0.408 min, m/z =378.1. 0.149 I-255 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-3-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2-one 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.42 (s, 1 H), 8.34 (d, J = 4.8 Hz, 1 H), 7.26 (d, J = 4.8 Hz, 1 H),6.90 (t, J = 51.6 Hz, 1 H), 5.63-5.37 (m, 2 H), 3.13- 3.06 (m, 1 H),2.92-2.80 (m, 2 H), 1.36 (d, J = 6.4 Hz, 3 H) LCMS RT = 0.583 min, m/z =378.2. 0.036 I-256 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-4-methyl-1,2,3,4-tetrahydro-1,7-naphthyridin-2-one 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.45-8.34 (m, 2 H), 7.25 (d, J = 4.8 Hz, 1 H), 6.89 (t, J = 51.6 Hz,1 H), 5.62-5.47 (m, 2 H), 3.27-3.20 (m, 1 H), 2.94-2.82 (m, 1 H),2.67-2.56 (m, 1 H), 1.40 (d, J = 6.8 Hz, 3 H) LCMS RT = 0.580 min, m/z =378.2. 0.057 I-257 Example 14

  N-[5-(difluoromethoxy)pyridin-3-yl]-N-({2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-5-yl}methyl)ethane-1-sulfonamide 1H NMR (400 MHz, CD3OD) δ 8.48(d, J = 2.4 Hz, 1 H), 8.40 (d, J = 2.4 Hz, 1 H), 7.90 (s, 1 H), 7.77 (t,J = 2.4 Hz, 1 H), 7.23 (t, J = 51.6 Hz, 1 H), 6.97 (t, J = 72.8 Hz, 1H), 5.35 (s, 2 H), 3.31 (q, J = 7.6 Hz, 2 H), 1.41 (t, J = 7.6 Hz, 3 H)LCMS RT = 1.251 min, m/z = 468.2. 0.231 I-258 Example 15

  3-({5-[5-(difluormethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1H-pyrrolo[2,3- c]pyridin-2-ol 1H NMR (400MHz, CD3OD) δ 8.40 (s, 1 H), 7.65 (s, 1 H), 7.50 (d, J = 6.8 Hz, 1 H),7.17 (t, J = 51.6 Hz, 1 H), 6.94 (d, J = 6.8 Hz, 1 H), 4.27 (s, 2 H)LCMS RT = 0.778 min, m/z = 350.2. 0.069 I-259 Example 14

  N-(5-chloropyridin-3-yl)-N-((2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-5-yl]methyl)ethane-1-sulfonamide 1H NMR (400 MHz, CD3OD) δ 8.55-8.51 (m, 2 H), 8.05 (t, J = 2.4 Hz, 1 H), 7.92 (s, 1 H), 7.25 (t, J =51.6 Hz, 1 H), 5.36 (s, 2 H), 3.34 (q, J = 7.2Hz, 2 H), 1.42 (t, 1 = 7.6Hz, 3 H) LCMS RT = 1.273 min, m/z = 436.2. 0.121 I-260 Example 14

  N-({2-[5-(difluorometiiyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-5-yl}methyl)-N-(pyridin-3- yl)ethane-1-sulfonamide 1HNMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.4 Hz, 1 H), 8.52-8.48 (m, 1 H),7.98 (s, 1 H), 7.87-7.66 (m, 1 H), 7.56 (t, J = 51.2 Hz, 1 H), 7.45-7.42(m, 1 H), 5.34 (s, 2 H), 3.37 (q, J = 7.2 Hz, 2 H), 1.30 (t, J = 7.2 Hz,3 H) LCMS RT = 0.821 min, m/z = 402.2. 0.333 I-261 Example 14

  N-(3-chlorophenyl)-N-({2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-5-yl}methyl)ethane-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 8.00(s, 1 H), 7.56 (t, J = 51.2 Hz, 1 H), 7.41- 7.36 (m, 4 H), 5.32 (s, 2H), 3.36 (q, J = 7.2 Hz, 2 H), 1.29 (t, J = 8.0 Hz, 3 H) LCMS RT = 1.554min, m/z = 435.1. 0.089 I-262 Example 14

  N-(5-chloropyridin-3-yl)-N-({2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-5-yl}methylmethanesulfonamide 1H NMR (400 MHz, CD3OD) δ 8.61-8.47 (m, 2 H), 8.05 (t, J = 2.4 Hz, 1 H), 7.93 (s, 1 H), 7.23 (t, J =51.6 Hz, 1 H), 5.32 (s, 2H), 3.16 (s, 3H) LCMS RT = 1.643 min, m/z =422.1. 0.110 I-263 Example 14

  N-({2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-5-yl}methyl)-N-(5- fluoropyridin-3-yl)methanesulfonamide1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1 H), 8.46 (d, J = 2.4 Hz, 1 H), 7.93(s, 1 H), 7.88-7.82 (m, 1 H), 7.23 (t, J = 51.6 Hz, 1 H), 5.33 (s, 2 H),3.16 (s, 3 H) LCMS RT = 1.478 min, m/z = 406.1. 0.108 I-264 Example 14

  N-({2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-5-yl}methyl)-N-(5-fluoropyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CD3OD) δ 8.48(s, 1 H), 8.45 (d, J = 2.8 Hz, 1 H), 7.91 (s, 1 H), 7.86-7.80 (m, 1 H),7.24 (t, J = 51.6 Hz, 1 H), 5.35 (s, 2 H), 3.31 (q, J = 7.2 Hz, 2 H),1.41 (t, J = 7.6 Hz, 3 H). LCMS RT = 1.618 min, m/z = 420.2. 0.087 I-265Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-[5- (trifluoromethoxy)pyridin-3-yl]methanesulfonamide 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 2.0 Hz, 1H), 8.56 (s, 1 H), 8.44 (s, 1 H), 7.80 (s, 1 H), 6.92 (t, J = 51.6 Hz, 1H), 5.30 (s, 2 H), 3.11 (s, 3 H) LCMS RT = 1.950 min, m/z = 472.1. 0.048I-266 Example 4

  2-cyano-N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-N-(pyridin-3-yl)ethane-1-sulfonamide 1H NMR (400 MHz, CD3OD) δ 8.70 (d, J= 2.8 Hz, 1 H), 8.52 (d, J = 3.6 Hz, 1 H), 8.44 (s, 1 H), 8.07-8.01 (m,1 H), 7.54-7.49 (m, 1 H), 7.21 (t, J = 51.6 Hz, 1 H), 5.41 (s, 2 H),3.72 (t, J = 7.2 Hz, 2 H), 3.05 (t, 1 = 7.2 Hz, 2 H). LCMS RT = 1.287min, m/z = 426.8. 0.042 I-267 Example 4

  N-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl)methyl)-N-[5-(trifluoromethoxy)pyridin-3-yl]ethane-1- sulfonamide 1H NMR (400 MHz,CDCl3) δ 8.71 (s, 1 H), 8.54 (s, 1 H), 8.41 (s, 1 H), 7.79 (s, 1 H),6.92 (t, J = 51.6 Hz, 1 H), 5.30 (s, 2 H), 3.22 (q, J = 7.6 Hz, 2 H),1.45 (t, J = 7.6 Hz, 3 H) LCMS RT = 0.328 min, m/z = 486.1 0.044 I-268Example 4

  3-[({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)(pyridin-3- yl)sulfamoyl]propanamide 1H NMR(400 MHz, CDCl3) δ 8.75 (d, J = 2.4 Hz, 1 H), 8.62-8.55 (m, 1 H) 8.39(s, 1 H), 7.90-7.84 (m, 1 H), 7.40- 7.33 (m, 1 H), 6.91 (t, J = 52.0 Hz,1 H), 5.27 (s, 2 H), 3.58 (t, J = 7.2 Hz, 2 H), 2.81 (t, J = 7.2 Hz, 2H). LCMS RT = 0.783 min, m/z = 444.9. 0.013 I-269 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl]methyl)- 1H,2H,3H,4H,5H-pyrido[3,4-b]azepin-2-one1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1 H), 8.46 (s, 1 H), 8.38 (s, 1 H),7.28 (s, 1 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.36 (s, 2 H), 2.84 (t, J =6.8 Hz, 2 H), 2.49- 2.37 (m, 2 H), 2.37-2.23 (m, 2 H). LCMS RT = 1.043min, m/z = 378.2 0.018 I-270 Example 2

  1-({5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,3-thiazol-2-yl}methyl)-1,2,3,4- tetrahydroquinoline 1H NMR (400MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.51 (t, J = 51.2 Hz, 1 H), 7.00- 6.90(m, 2 H), 6.60-6.55 (m, 2 H), 4.86 (s, 2 H), 3.47 (t, J = 5.6 Hz, 2 H)2.75 (t, J = 6.0 Hz, 2 II), 2.02-1.92 (m, 2 H) LCMS RT = 1.769 min, m/z= 349.2 0.539

TABLE 4 Characterization Data and HDAC6 Activity for Compounds ofFormula (II), Formula (III), Formula (IV), and Formula (A). HDAC6 Cmpd¹H NMR IC₅₀ ID Structure/Name MS (m/z) (RT) (μM) II-1 Example 16

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-morpholino-2-oxoethyl)pyridin-2(lH)-one ¹H NMR (400 MHz, DMSO-d₆) δppm 7.83 (br d, J = 7.09 Hz. 1 H) 7.37-7.73 (m, 1 H) 6.99 (s, 1 H) 6.81(br d. J = 6.85 Hz, 1 H) 4.92 (s, 2 H) 3.42-3.71 (m 8 H, overlaps withwater peak). LCMS: RT = 2.29 min, m/z = 341.1 0.592 II-2 Example 16

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-oxo-2-(pynoIidin-1-yl)ethyl)pyridin-2(1H)- one ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.83 (br d, J = 7.09 Hz. 1 H) 7.38-7.74 (m, 1 H) 6.99 (s,1 H) 6.80 (br d. .7 = 6.60 Hz, 1 H) 4.80 (s, 2 H) 3.53 (brt, .7 = 6.60Hz, 2 H) 3.28-3,36 (m, 2 H, overlaps with water peak) 1.89-2.00 (m, 2 H)1.74-1.88 (m, 2 H) LCMS: RT = 2.82 min, mz = 325.1 0.987 II-3 Example 17

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1- methylpyridin-2(1H)-one¹H NMR (400 MHz, chloroform-d) δ ppm 7.48 (br d, J = 6.60 Hz, 1 H) 7.27(s, 1 H, overlaps with CHCl₃) 6.73-7.11 (overlapping m, 2 H) 3.62 (br s,3 H) LCMS: RT = 2.66 min, m/z = 228.1 0.158 II-4 Example 17

1-benzyl-4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)pyridin-2(1H)-one¹H NMR (400 MHz, chloroform-d) δ ppm 7.19-7.50 (overlapping m, 7 H)6.74-7.10 (overlapping m, 2 H) 5.19 (s, 2 H) LCMS: RT = 4.21 min, m/z =304.1 0.337 II-5 Example 17

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-phenethylpyridin-2(1H)-one ¹H NMR (400 MHz, chloroform-d) δ ppm7.21-7.38 (m, 5 H) 7.14 (br d, J = 7.09 Hz, 1 H) 6.75-7.07 (overlappingm, 2 H) 6.65 (br d, J = 6.85 Hz, 1 H) 4.21 (br t, J = 6.85 Hz, 2 H) 3.10(br t, J = 6.85 Hz, 2 H) LCMS: RT = 4.39 min. m/z = 318.1 0.245 II-6Example 16

4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2(1H)-one ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.17 (br s, 1H) 7.67 (br d, J = 6.11 Hz, 1 H)6.96 (br s, 1 H) 6.73 (br d, J = 5.14 Hz, 1 H) LCMS: RT = 2.93 min m/z =232.0 1.1 II-7 Example 16

tert-butyl 2-(2-oxo-4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-1(2H)-yl)acetate ¹H NMR (400 MHz,chloroform-d) δ ppm 7.42 (br d, J = 7.09 Hz, 1 H) 7.27 (br s, 1 H,overlaps with (HCl) 6.83-6.93 (m, 1 H) 4.61 (s, 2 H) 1.50 (s, 9 H) LCMS:RT = 4.66 min, m/z = 368.1 0.742 II-8 Example 17

1-methyl-4-(5-(trifluoromethyl)-1,3,4- oxadiazol-2-yl)pvridin-2(1H)-one¹H NMR (400 MHz, chloroform-d) δ ppm 7.50 (br d, J = 6.85 Hz. 1 H) 7,26(s, 1 H, overlaps with CHCl₃) 6.85 (br d, J = 6.36 Hz, 1 H) 3.63 (s, 3H) LCMS: RT = 3.43 min, m/z = 246.0 4 II-9 Example 17

¹H NMR (400 MHz, chloroform-d) δ ppm 7.07-7.40 (overlapping m, 7 H)6.60-6.73 (m, 1 H) 4.21 (brt, J = 6.85 Hz, 2 H) 3.10 (br t J = 6.60 Hz,2 H) LCMS: RT = 4.88 min. m/z = 336.1 4.3 II-10 Example 16

2-(4-(5-(difluoromethyl)-1,3.4-oxadiazol-2-y))-2-oxopyridin-1(2H)-yl)acetic acid ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.94 (br d, J = 7.09 Hz, 1 H) 7.39-7.74 (m, 1 H) 7.02 (s, 1 H) 6.83(brd, J = 7.09 Hz, 1 H) 4.71 (s, 2 H) LCMS: RT = 2.52 min, m/z = 272.03.2 II-11 Example 16

tert-butyl 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)acetate ¹H NMR (400 MHz,chloroform-d) δ ppm 7.40 (d, J = 7.09 Hz, 1 H) 7.29 (s, 1 H) 6.76-7.10(overlapping m, 2 H) 4.61 (s, 2 H) 1.49 (s, 9 H) LCMS: RT 4.20 mm, m/z =350.1 0.145 II-12 Example 16

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2(1H)-one ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.13 (br s, 1 H) 7.38-7.73 (overlapping m, 2H) 6.92 (s, 1 H) 6.72 (br d, J = 6.36 Hz, 1 H). LCMS: RT = 1.15 min, m/z= 214.0 0.810 II-13 Example 19

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-((6-methylpyridin-3-yl)oxy)ethyl)pyridin- 2(1H)-one ¹H NMR (400 MHzCDCl₃) δ 8.16 (s. 1 H), 7.64 (d, J = 7.2 Hz, 1 H), 7.29 (s, 1 H),7.08-7.05 (m, 2 H), 6.93-6.86 (m, 2 H), 4.43-4.38 (m. 2 H). 4.36-4.32(m, 2 H), 2.48 (s, 3 H). LCMS RT = 1.256 min, m/z = 349.2. 0.024 II-14Example 19

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-(3,5-difluorophenoxy)ethyl)pyridin-2(1H)- one ¹H NMR (400 MHz, CDCl₃)δ 7.59 (d, J = 7.2 Hz. 1 H), 7.29 (s, 1 H), 7.08-6.88 (m, 2 H),6.43-6.38 (m, 3 H), 4.41-4.37 (m, 2 H), 4.34-4.27 (m, 2 H). LCMS R_(T) =0.861 min, m/z = 370.2. [M + H]⁺ LCMS RT = 0.861 min, m/z = 370.2. 0.003II-15 Example 18

1-((2-cyclopropylpyridin-4-yl)methyl)-4-(5-(difluoromethy))-1,3,4-oxadiazol-2-yl)py ridin- 2(1H)-one ¹H NMR (400MHz, CDCl₃) δ ppm 8.42 (d, J = 5.2 Hz, 1 H), 7.46 (d, J = 12 Hz, 1 H),7.35 (s, 1 H), 7.07-6.75 (m, 4 H), 5.15 (s, 2 H), 2.03-1.94 (m. 1 H).1.07- 0.96 (m, 4 H) LCMS RT = 0.358 min, m/z = 345.2 0.103 II-16 Example19

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1-(2-(3-fluorophenoxy)ethyl)pyridin-2(1H)-one ¹H NMR (400 MHz, CDl₃) δ ppm7.64 (d, J = 7.2 Hz, 1 H), 7.30-7.22 (m 2 H), 6.92-6.80 (m, 2 H),6.71-6.66 (m 3 H), 4.43-4.38 (m, 2 H), 4.35-4.31 (m, 2 H) LCMS RT =0,837 min, m/z = 352.2 0.002 II-17 Example 20

5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-(2-(3-fluorophenoxy)ethyl)pyridazin-3(2H)- one ¹H NMR (400 MHz, CDCl₃) δppm 8.48 (d, J = 2.4 Hz, 1 H), 7.56 (d, J = 2.4 Hz, 1 H), 7.24-7.18 (m,1 H), 6.96 (t J = 51.6 Hz, 1 H), 6.69-6.59 (m, 3 H), 4.64 (t, J- 5.2 Hz,2 H), 4.41 (t. J = 5.2 Hz, 2 H) LCMS RT = 0.846 min, m/z = 353.2 0.009II-18 Example 16

2-(4-(5-(difluoromethyl)-1,3.4-oxadiazol-2-yl)-2-oxopyridin-1(2H)-yl)-N- phenylacetamide ¹H NMR (400 MHz, DMSO -d₆) δ ppm 10.4 (s, 1 H), 7.95 (d, J = 7.2 Hz, 1 H), 7.70-7.45 (m, 3 H),7.32 (t, J= 8.0 Hz, 2 H), 7.10-7.02 (m, 1 H), 7.00 (s, 1 H), 6.86-6.82(m, 1 H), 4.84 (s, 2 H) LCMS R_(T) = 0.931 min, m/z = 346.9 0.218 II-19Example 21

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-1- (((IR,2R)-2-phenylcyclopropyl)methyl)pyridin-2(1H)-one ¹H NMR (400 MHz, CDCl₃) δ7.58 (d, J = 6.8 Hz 1 H), 7.32-7.27 (m, 2 H), 7.24 (s, 1 H), 7.21-7.15(m, 1 H), 7.09- 7.03 (m, 2 H), 7.02-6.77 (m, 2 H), 4.14- 3.97 (m, 2 H),2.12-1.99 (m, 1 H), 1.65-1.60 (m, 1 H), 1.13 (t. J = 7.6 Hz, 2H). LCMSR_(T) = 0.929 min, m/z = 344.2 0.023 IVa-1 Example 25

3-chloro-N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N- methylaniline ¹H NMR (400MHz, CDC1₃) δ 7.17 (t, J = 8.4 Hz. 1 H). 7.06-6.93 (m, 1 H), 6.80-6.61(m, 4 H), 4.74 (s. 2 H). 3.31 (s, 3 H). LCMS RT = 1.331 min, m/z = 341.10.255 IVa-2 Example 23

N-({3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)-N-(pyridin-3- yl)ethane-1-sulfonamide ¹H NMR(400 MHz, CDCl₃) δ 8.64- 8.62 (m, 2 H), 7.77-7.74 (m, 1 H), 7.40- 7.37(m, 1 H), 7.08-6.82 (m, 2 H), 5.14 (s, 2 H), 3.17 (q, J = 7.2 Hz, 2 H),1.45(1, J = 7.6 Hz, 3 H). RT = 1.119 mm, m/z = 386.1. 0.0821 IVa-3Example 23

N-(3-chlorophenyl)-N-({3-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)ethane-1-sulfonamide ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.23 (m 4 H), 7.09-6.80 (m, 2 H), 5.11 (s, 2 H), 3.14 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 8.0 Hz, 3 H). RT = 1.954 min, m/z = 418.8 0.012 IVa-4Example 23

N-(3-chlorophenyl)-N-({3-[5- (difluoromethyl)-1,3,4-oxadiazol-2-yl]-1,2-oxazol-5-yl}methyl)cyclopropanesulfonamide ^(l)H NMR (400 MHz, CDCl₃) δ7.36 (s, 1 H). 7.35-7.30 (m, 3 H), 6.94 (t, J = 51.6 Hz, 1 H), 6.93 (s,1 H), 5.11 (s, 2 H), 2.51-2.43 (m, 1 H), 1.13-1.10 (m, 2 H), 1.06-1.01(m, 2 H). RT = 1.921 min. m/z = 431.1. 0.022 IVb-1 Example 22

N-(3-chlorophenyl)-N-((5-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)ethanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ ppm7.34 (s, 1 H), 7.29-7.21 (m. 4 H), 6.91 (t, J = 51.6 Hz, 1 H), 5.02 (s,2 H), 3.12 (q, J = 7.6 Hz. 2 H). 1.40 (t, J = 7.6 Hz, 3 H) LCMS: RT =3.179 min, m/z = 419.1 0.037 IVb-2 Example 24

3-chloro-N-({5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)isoxazol-3-yl)methyl)-N- methylaniline ¹H NMR (400 MHz,DMSO - d₆) δ 7.57 (t, J = 51.2 Hz, 1 H), 7.42 (s, 1 H), 7.18 (t, J = 8.0Hz, 1 H), 6.83-6.63 (m, 3 H), 4.80 (s, 2H). 3.07 (s, 3 H). LCMS: RT =2.277 min, m/z = 341.0 0.518 IVb-3 Example 24

3-chloro-N-({5-[5-(difluoromethyl)-1,3,4- oxadiazol-2-yl]-1,2-oxazol-3-yl}methyl)aniline ¹H NMR (400 MHz, CD₃OD) δ 7.19- 7.12 (m, 2 H),7.01-6.94 (m, 1 H), 6.53- 6.50 (m, 3 H), 4.41 (s, 2 H). RT = 0.983 min,m/z = 327.0. 1.4 A-1 Example 26

5-(6-((1- (2,6difluorophenyl)cyclopropyl)amino)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole-2- carbonitrile ¹H NMR (400 MHz,CDCl₃) δ = 8.68 (s, 1H), 7.73 (d, J = 11.2 Hz, 1H), 7.19 (m, 1H), 6.84(m, 2H), 6.08 (br s, 1H), 1.40 (m, 4H) m/z = 358.0 A-2 Example 27

2-(2-benzylpyrazolo[1,5-a]pyrimidin-6-yl-5-(difluoromethyl)-1,3,4-oxadiazole ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H) 9.06 (s. 1 H). 7.40-7.10 (m, 5 H), 6.96 (t, J = 51.6 Hz, 1 H), 6.21(s, 1 H), 4.25 (s, 2 H) LCMS RT = 4.160 min, m/z = 328.2 0.346

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is S; R^(a)is selected from the group consisting of H, halogen, and C₁₋₃ alkyl; R¹is

R² is selected from the group consisting of alkyl, alkoxy, andcycloalkyl, each of which is optionally substituted; R³ is H or alkyl;R⁴ is selected from the group consisting of alkyl, —(SO₂)R²,—(SO₂)NR²R³, and —(CO)R²; and R⁵ is heteroaryl.
 2. The compound of claim1, wherein R^(a) is H.
 3. The compound of claim 1, wherein R¹ is


4. The compound of claim 1, wherein R⁴ is —(SO₂)R².
 5. The compound ofclaim 4, wherein —(SO₂)R² is —(SO₂)alkyl, —(SO₂)alkyleneheterocyclyl,—(SO₂)haloalkyl, —(SO₂)haloalkoxy, or —(SO₂)cycloalkyl.
 6. The compoundof claim 1, wherein the heteroaryl is a 5- to 6-membered heteroaryl. 7.The compound of claim 6, wherein the 5- to 6-membered heteroaryl isselected from the group consisting of

wherein R^(b) is halogen, alkyl, alkoxy, cycloalkyl, —CN, haloalkyl, orhaloalkoxy; and m is 0 or
 1. 8. The compound of claim 7, wherein R^(b)is F, Cl, —CH₃, —CH₂CH₃, —CF₃, —CHF₂, —CF₂CH₃, —CN, —OCH₃, —OCH₂CH₃,—OCH(CH₃)₂, —OCF₃, —OCHF₂, —OCH₂CF₂H, and cyclopropyl.
 9. A compound ofFormula (Ik):

or a pharmaceutically acceptable salt thereof, wherein: R^(b) is H,halogen, alkyl, cycloalkyl, —CN, haloalkyl, or haloalkoxy; and R⁴ isalkyl, alkoxy, haloalkyl, or cycloalkyl, each of which is optionallysubstituted.
 10. The compound of claim 9, wherein R^(b) is H, halogen,haloalkyl, or haloalkoxy.
 11. The compound of claim 9, wherein R⁴ isoptionally substituted alkyl or cycloalkyl.
 12. The compound of claim 9,having the structure:

or a pharmaceutically acceptable salt thereof, wherein: R^(b) is H,halogen, alkyl, cycloalkyl, —CN, haloalkyl, or haloalkoxy; and R⁴ isalkyl, alkoxy, haloalkyl, or cycloalkyl, each of which is optionallysubstituted.
 13. The compound of claim 12, wherein R^(b) is H, halogen,haloalkyl, or haloalkoxy.
 14. The compound of claim 12, wherein R⁴ isoptionally substituted alkyl or cycloalkyl.
 15. The compound of claim14, wherein R⁴ is alkyl.
 16. The compound of claim 9, having thestructure:

or a pharmaceutically acceptable salt thereof, wherein: R^(b) is H,halogen, alkyl, cycloalkyl, —CN, haloalkyl, or haloalkoxy; and R⁴ isalkyl, alkoxy, haloalkyl, or cycloalkyl, each of which is optionallysubstituted.
 17. The compound of claim 16, wherein R^(b) is H, halogen,haloalkyl, or haloalkoxy.
 18. The compound of claim 16, wherein R⁴ isoptionally substituted alkyl.
 19. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1 of formula:

or a pharmaceutically acceptable salt thereof.